Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes

Size: px
Start display at page:

Download "Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes"

Transcription

1 Physiol Genomics 8: , First published December 4, 2001; /physiolgenomics Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes STEPHEN B. HARRAP, 1 ZILLA Y. H. WONG, 1 MARGARET STEBBING, 1 ANGELA LAMANTIA, 1 AND MELANIE BAHLO 2 1 Department of Physiology, The University of Melbourne, and 2 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3010, Australia Received 15 August 2001; accepted in final form 26 November 2001 Harrap, Stephen B., Zilla Y. H. Wong, Margaret Stebbing, Angela Lamantia, and Melanie Bahlo. Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes. Physiol Genomics 8: , First published December 4, 2001; / physiolgenomics Understanding genetic factors that contribute to population-wide variation in blood pressure is likely to benefit prevention and treatment of cardiovascular disease. The aim of the Victorian Family Heart Study is to identify genes for cardiovascular risk in 783 volunteer adult families recruited from the general population. In this preliminary study we sought to identify quantitative trait loci (QTLs) using a genome-wide linkage analysis in 274 adult sibling pairs of average age 24 yr selected without respect to blood pressure. We compared multipoint linkage results for carefully measured systolic (SBP) and diastolic (DBP) pressures before and after statistical adjustment for covariation with sex, oral contraception, age, height, and weight. The average BP was 123/67 (SD: 12/11) mmhg in males (n 283) and 114/64 (SD: 10/9) mmhg in females (n 265). Nonparametric Z-scores from multipoint GeneHunter II analysis were suggestive (3.1 or more) at four QTLs for SBP (chromosomes 1, 4, 16, and X) but at no QTLs for DBP. Most Z-scores were affected little by adjustment for covariates. However, the SBP QTL on chromosome 16 was obvious only for unadjusted pressures. This population-based quantitative trait analysis has identified more QTLs than any of the eight previous genome-wide scans for blood pressure. Considerable discrepancies between different studies may reflect the presence of false-positive results or real biological differences between populations. quantitative trait loci; systolic blood pressure; cardiovascular risk Article published online before print. See web site for date of publication ( Address for reprint requests and other correspondence: S. B. Harrap, Dept. of Physiology, Univ. of Melbourne, Victoria 3010, Australia ( s.harrap@unimelb.edu.au). A MOLECULAR UNDERSTANDING of the genetic basis of variation in blood pressure is relevant to the development of new strategies to prevent and treat high blood pressure and related cardiovascular complications. Genome scans offer a comprehensive search for genetic loci that may be worthy of further detailed analyses for gene identification and mutation detection. In this study we present the results of a preliminary genomewide search for blood pressure quantitative trait loci (QTLs) in white families drawn from the general population and report the position of four QTLs for systolic blood pressure. These QTLs span a number of important candidate genes. We also report that evidence in favor of linkage at one systolic blood pressure (SBP) QTL disappeared after adjustment for sex and body size. Finally, we compare the results of published genome scans and consider their similarities and differences. MATERIALS AND METHODS This study is a core component of the Victorian Family Heart Study (VFHS). The details of the recruitment and phenotyping in the VFHS have been described in detail elsewhere (7). In brief, the aim of the VFHS was to recruit white families that represent the population range of cardiovascular risk phenotypes including blood pressure. Recruitment was population based, and the cardiovascular risk phenotypes of our subjects were typical of the general Australian community (7). A family history of heart disease was not relevant to recruitment. Families comprised, at a minimum, a mother and father with at least one natural child. A family was eligible if both parents were aged between 40 and 70 yr and at least one offspring was aged between 18 and 30 yr. Other offspring were also included if they were aged between 18 and 30 yr. The lower age threshold for offspring was set to minimize the confounding effects of growth on the phenotypes under study. A total of 783 families, comprising a total of 2,959 individuals, were recruited between 1991 and 1996 (7). Selection of sibling pairs. The aim of this analysis was to screen the genome for QTLs that could be studied in greater detail in larger numbers of families at a later stage. For this first-pass screen we selected a total of 275 sibling pairs. These pairs were selected at random from recruited families that had two or more children. Only one pair was recruited from each family, assuring independence of pairs (2). Known monozygotic twins or twins of the same sex with uncertain zygosity were excluded from the linkage analyses. Following the linkage analysis, error checking (see below) revealed that one pair was in fact monozygotic twins. This pair was excluded, and the data reported here refers only to the remaining 274 sibling pairs. Phenotype measurement. These studies were approved by the Ethics Review Committee of the Alfred Hospital, Melbourne, and informed consent was obtained from all participants. Participants attended one of our study research clinics between 9 AM and 7 PM. Weight and height were measured after removing heavy clothing and shoes. Subjects then /02 $5.00 Copyright 2002 the American Physiological Society 99

2 100 BLOOD PRESSURE GENES rested supine for 10 min, during which time a suitably sized sphygmomanometer cuff was applied to the right arm. Blood pressures were measured by carefully trained research nurses using a standard mercury sphygmomanometer and were subject to routine quality control checks. SBP was taken at the return of arterial sounds (Korotkoff phase I) and diastolic blood pressure (DBP) at the disappearance of sounds (Korotkoff phase V). Blood pressure measurements were made to the nearest 2 mmhg. Three measurements of SBP and DBP were taken. The first reading was discarded to avoid potential bias, and the last two were recorded and averaged to give values for SBP and DBP used in these analyses. Detailed information was obtained regarding treatment with oral contraceptive or hormone replacement therapy, antihypertensive medications, and lipid-lowering therapy. Following phenotypic measurements, venous blood was collected for DNA extraction. Phenotype standardization and adjustment. The primary linkage analysis was planned for raw blood pressures in the 274 sibling pairs of the offspring generation. A secondary linkage analysis was planned to utilize blood pressure phenotypes that had been standardized and adjusted for the effects of important covariates associated with blood pressure in this group. To obtain the most representative estimates of these covariate effects, we used data from the entire group of 1,410 offspring. Both SBP and DBP were significantly different in males (n 674, 122/67 mmhg) and females (n 736, 114/65, P ) and between women taking (n 320, 116/66 mmhg) or not taking (n 416, 112/64 mmhg, P ) oral contraception. Therefore, SBP and DBP data were initially standardized as Z-scores (SBPZ and DBPZ, respectively, calculated by dividing the difference between each individual value and the group mean by the standard deviation for the group) within each of three separate groups: men, women taking oral contraception, and women not taking oral contraception. The only exceptions to this standardization procedure were subjects taking antihypertensive medications. In such cases (5 of the 1,410 total offspring) we assumed that the recorded pressures were not necessarily reliable indicators of untreated pressures and would otherwise be expected to be in the upper 10% of the distribution. Therefore, as in previous studies (21) where SBPZ and DBPZ on treatment fell below the 90th percentile (Z 1.64) the value of 1.64 was substituted. This situation applied to only one female in the sibling pair analysis (see below). SBPZ and DBPZ from the three groups were combined for further adjustment. Age correlated with DBPZ (n 1,410, Spearman r 0.20, P ), and DBPZ was adjusted by regression on age. Finally, sex-standardized values of weight and height were considered. Stepwise multiple regression analysis was used to adjust SBPZ and DBPZ for weight (for SBPZ, 0.22, P ; for diastolic, 0.23, P ) and DBPZ for height (for DBPZ, 0.15, P ). The final adjusted phenotypes (as standardized residuals) were used for the secondary linkage analysis. Genome-wide linkage mapping. DNA from the sibling pairs was extracted and purified. We used the ABI PRISM Human Linkage Mapping Set version 2, which comprises 400 microsatellite markers with approximately a 10-cM resolution. The markers are organized into 28 panels that cover all 22 autosomes and the X chromosome. PCR primer pairs were labeled with the HEX, FAM, or NED fluorescent dyes to enable differentiation of overlapping alleles. The application of the mapping set was undertaken by the Australian Genome Research Facility. All microsatellites were amplified according to manufacturer s instructions (Perkin-Elmer) using PCR robots, the resulting products were visualized on ABI PRISM 377 gene sequencers (Perkin-Elmer), and alleles were sized using GeneScan Analysis Version 2.1 and Genotyper Version 2.0 (Perkin-Elmer). Linkage analyses. We used the genotyping data from the sibling pairs to investigate the likely chromosomal location of QTLs linked with the phenotypes. The parents of the sibling pairs were not genotyped, and identity-by-descent (IBD) information was inferred from only the sibling pair data using multipoint methods and microsatellite markers that are highly informative. GeneHunter II (11) was employed to perform a multipoint nonparametric linkage analysis using the information from all genetic markers jointly to infer the full probability distribution of IBD status. The probability of linkage was expressed as nonparametric Z-scores. Error checking. The data were checked for pedigree errors, and one sibling pair was identified as being monozygotic twins and was thus excluded from the linkage analyses (see above). Genotyping errors arise in all genetic studies and may contribute to false-positive or false-negative linkage results. Such errors are usually detected by checking data for compliance with Mendelian inheritance rules. Apart from limited checking of the X chromosome, Mendelian error checking is not possible in the absence of parental genotypes in sibling pair studies. To find gross genotyping errors, we employed an alternative strategy that detects likely double recombinants using the program SIBLODERR (1), which is based on previously published algorithms (17). The program automatically replaces alleles found to be in error with a missing value allele. This technique was applied to all the autosomes. The sex chromosome data was checked using standard Mendelian inheritance rule, according to which there is a maximum of three different alleles at each marker in any sibling pair. On the genome-wide scan mapping data, we detected 1,254 genotyping errors, which equates to a detected genotyping error rate of 0.268%. The data appear to be robust since reanalysis of the data after the removal of these errors only led to minor changes in linkage results. Other statistical analyses. Descriptive statistics are presented as means with SD unless specified otherwise. Comparisons between group means were undertaken using t- tests after checking normality of data and homogeneity of variance and applying the Bonferroni correction for multiple testing. For the identification of important blood pressure covariates, we employed multiple regression methods. Relationships were analyzed by stepwise regression, but similar results were obtained when all variables were entered simultaneously. The regression analyses were also used to adjust for the effects of covariates and standardize the residuals as described above. The distribution of all standardized and adjusted estimates were checked for normal distribution with a mean of zero and unit variance. Statistical procedures were performed using SPSS version 6.0 for the Power Macintosh. RESULTS Subject characteristics. Table 1 presents the basic characteristics of the 548 individuals who comprised the 274 sibling pairs and compares them with all 1,410 offspring in the VFHS. As reported previously, the VFHS subjects are representative of the general Australian population (7). The phenotypes of the selected sibling pairs resembled closely those of the complete set of VFHS offspring. Figure 1 shows the distribution

3 BLOOD PRESSURE GENES 101 Table 1. Relevant phenotypes in the Victorian Family Heart Study in men and women of all 1,410 offspring and the 548 offspring included as the 274 sibling pairs in the genome scan All Offspring Genome Scan Offspring Men Women Men Women n Age, yr (3.78) (3.63) (3.72) (3.50) Height, cm (6.64) (6.59) (6.45) (7.45) Weight, kg (12.34) (10.58) (12.44) (10.10) DBP, mmhg (10.78) (9.16) (10.89) (9.07) SBP, mmhg (11.15) (9.88) (11.67) (9.56) Values are means; SD are in parentheses. SBP, systolic blood pressure; DBP, diastolic blood pressure. of measured SBP (Fig. 1A) and DBP (Fig. 1B) for the 548 individuals. Of the 548 subjects, two women were being treated for hypertension. Blood pressure in one was below the 90th percentile, and she was given SBPZ and DBPZ of 1.64 (see MATERIALS AND METHODS). The sex distribution was relatively even, with 283 men and 265 women. Within the pairs there was a relatively even balance of the sexes, with 65 malemale, 135 male-female, and 74 female-female pairs. The distributions of the absolute values for SBP and DBP differences between sibling pairs are shown in Fig. 1, C and D, respectively. The median for the absolute difference in SBP pressure between siblings was 10 mmhg with an interquartile range of 4 16 mmhg. For absolute differences in DBP between siblings, the median value was 8 mmhg and the interquartile range was 4 13 mmhg. Genome linkage. Figures 2 and 3 show the probability plots of nonparametric Z-score values for linkage of SBP and DBP, respectively, across all 22 autosomes and the X chromosome. Figures 2 and 3 show data from linkage analyses of raw (thick line) and adjusted (thin line) pressure phenotypes. In general, the Z-scores for these phenotypes describe similar curves, with some exceptions (see below). In this first-pass analysis, we identified suggestive QTLs as those with Z-scores of 3.1 or greater according to the guidelines of Lander and Kruglyak (13). Such values were observed for four loci associated with SBP (see Table 2 and Fig. 2). For SBP a Z-score peak of 3.5 on chromosome 1 spanned the markers D1S255, D1S2797, D1S2890, and D1S230. Another peak on chromosome 4 (Z 3.2) spanned markers D4S1534, D4S414, D4S1572, D4S406, D4S402, and D4S1575. On chromosome 16 in a region that spans the markers D16S3046, D16S3068, and D16S3136, a peak Z-score of 3.2 was seen for Downloaded from by on December 5, 2017 Fig. 1. Frequency distributions from 548 individuals comprising 274 sibling pairs of individual systolic blood pressures (SBP, mmhg; A), individual diastolic blood pressures (DBP, mmhg; B), absolute differences in systolic pressure (mmhg) between siblings (C), and absolute differences in diastolic pressure (mmhg) between siblings (D).

4 102 BLOOD PRESSURE GENES Fig. 2. Z-score values for genome-wide scan of linkage for systolic blood pressure levels. Thick black lines represent raw pressure levels, thin black lines represent adjusted pressure levels (see text for details). unadjusted SBP. However, the Z-score peaked at only 1.4 for adjusted SBP (Fig. 2). Finally, on the X chromosome we observed a peak Z-score of 3.3 for raw SBP in a region that spanned the markers DXS1068, DXS993, and DXS991. DISCUSSION We undertook a preliminary genome-wide scan in search of chromosomal QTLs linked with population variation in blood pressure and to determine whether linkage results were influenced by important covariates. Based on evidence of suggestive genome-wide probabilities, this first-pass genome investigation located four QTLs that warrant closer attention, one of which showed evidence of dependence on blood pressure covariates. The relevant QTLs were observed on chromosomes 1, 4, 16, and X. The QTL on chromosome 1 (1p34.3-1p31) may be syntenic to a region on rat chromosome 5 that has been linked with blood pressure (4). The human candidates in this region include genes encoding the leptin receptor (LEPR) and the transforming growth factor- type III receptor (TGFBR3). It is noteworthy that the QTL on chromosome 1 does not include the angiotensinogen gene (AGT) at 1q42-q43, which has been suggested as relevant to hypertension (10). The observed QTL on chromosomes 4 (4q21-4q28) may be syntenic to blood pressure locus on rat chromosomes 2 (3), but no outstanding human candidate genes are known presently in this region. The QTL on chromosome 16 (16p p12) is consistent with our previous linkage results with a separate set of markers around the epithelial sodium channel - and -subunit genes (SCNN1B and SCNN1G) in this region (22). The SCNN1B and SCNN1G genes have been implicated in the etiology of Mendelian diseases associated with very high or very low blood pressures (16). However, there are also other relevant candidate genes in this region, including the genes encoding a norepinephrine transporter (SLC6A2) and the renal thiazide-sensitive NaCl transporter (SLC12A3) and the renal sodium-glucose cotransporter (SLC5A2). The SBP QTL on the X chromosome (Xp11.4-Xq11) coincides with a region that encompasses the candidate genes encoding the androgen receptor (AR), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and the renal voltage-gated chloride channel

5 BLOOD PRESSURE GENES 103 Fig. 3. Z-score values for genome-wide scan of linkage for diastolic blood pressure levels. Thick black lines represent raw pressure levels, thin black lines represent adjusted pressure levels (see text for details). Downloaded from (CLCN5). The X chromosome is the second human sex chromosome to be associated with blood pressure variation. We recently reported significant association of diastolic pressure with a polymorphism in the nonrecombining region of the Y chromosome (5). Interestingly, both the X and Y chromosomes have been linked with significant blood pressure variation in spontaneously hypertensive rats of the stroke-resistant and stroke-prone strains (6, 8). Recently a number of genome scans concerned with blood pressure have been reported (9, 12, 15, 18 20, 23, 24). Table 2 summarizes these studies by listing the QTLs that satisfy the genome-wide suggestive significance level, taken as a Z-score of 3.1 or greater, a log of the odds ratio (LOD) score of 2.2 or greater, or a P value of or less (13). The comparison of studies reveals a number of interesting features. Most studies have reported linkage with SBP rather than DBP. There is no obvious explanation for the lack of evidence of DBP QTLs. The number of QTLs detected varies between studies from zero QTLs in two studies in hypertensive sibling pairs (18, 20), to four QTLs in the present study. Issues of statistical power are of potential relevance here. by on December 5, 2017 Table 2. Summarized multipoint linkage results of genome scans for blood pressure No of QTLs Chromosomes Phenotype Ethnicity Reference Present study 4 1, 4, 16*, X SBP Caucasian Rice et al. 3 2, 5, 7 SBP Caucasian 19 Xu et al. 2 15, 16* DBP, SBP Chinese 23 Krushkal et al. 1 6 SBP Caucasian 12 Levy et al SBP Caucasian 15 Zhu et al. 1 2 SBP Chinese 24 Hseuh et al. 1 2 DBP Caucasian 9 Perola et al. 0 HT Caucasian 18 Sharma et al. 0 HT Caucasian 20 The number of quantitative trait loci (QTLs) given represents those for which the significance of linkage exceeded the genome-wide suggestive criteria of Lander and Kruglyak (13). HT, hypertension. * Possible overlap of the QTLs on chromosome 16 in these two studies.

6 104 BLOOD PRESSURE GENES Power may be limited by relatively small numbers of subjects. However, even some of the larger studies found only one QTL (15). The discrepancies in the locations of the QTLs between reported studies are striking. At only one QTL on chromosome 16 (present study and Ref. 23) does there appear to be any suggestion of similarity. There are a number of possible explanations for such inconsistency. One potential explanation is the use of different panels of map markers between the different scans. Another explanation is statistical. The level of statistical significance attributable to QTLs that satisfy suggestive linkage leads one to expect one falsepositive QTL per genome-wide scan (13). Only the present study and two of the previously published studies (19, 23) report more than one QTL at this level of significance. One study (15) reported a single QTL with a probability level well beyond the suggestive threshold. If one assumes the presence of one falsepositive per genome scan at this level of significance, then it is not surprising that many of reported QTLs do not coincide, particularly where limited numbers of QTLs are detected in individual studies. There may be other biological explanations for the incongruities between reported QTLs, such as underlying genetic and environmental variation between the populations studied. Should this prove to be the case, it raises doubts regarding the general applicability of individual QTLs that are not reproducible in different populations. The exact nature of the phenotype may also be important. The different linkage patterns of DBP and SBP may be a relevant example of the specificity of blood pressure phenotype. It is not certain whether more subtle differences, such as the posture in which blood pressures are measured, are important. In the published studies, blood pressures have been measured in the sitting position (9, 15, 24), but sometimes posture was unspecified (12, 19, 20, 23). In some studies covariates of blood pressure such as body size were taken into account (9, 15, 19); in others they were not. It appears from the findings in the present study that at some QTLs blood pressure covariates may have important effects on linkage results and potentially explain study discrepancies. For example, if sex and body size influence blood pressure independent of a particular blood pressure QTL, failure to adjust for their effects will blur linkage detection. We did not find substantial evidence of such an effect at any QTL. However, we found the reverse situation in relation to the chromosome 16 QTL at which the Z-score fell from 3.2 for unadjusted SBP to 1.4 for adjusted SBP. Such an effect might be explained if sex and body size interact cooperatively and specifically with genetic mechanisms encoded by the particular QTL. For example, the blood pressure effect of a QTL might be enhanced in the presence of increased body mass index, or a QTL might increase both blood pressure and body mass index. Under these circumstances, the adjustment of blood pressure for covariation in body mass index would diminish residual blood pressure variation attributable to such a QTL and limit the apparent strength of linkage. Finally, in light of the strong influence of growth on blood pressure in adolescence (14), linkage analyses that include younger subjects might reveal growth rather than blood pressure QTLs unless correction is made for growth effects. In summary, this genome scan reveals four QTLs for SBP and would, therefore, be consistent with the presumed polygenic nature of blood pressure variation. No QTLs for DBP were detected. We also found that the linkage probability of one QTL seemed to depend on association with sex and body size. Further multivariate analyses are required to clarify this possibility. Our study shows that it is possible to detect QTLs in sibling pairs selected at random from a representative population sample. Our deliberate epidemiological approach to sampling and recruitment is intended to identify QTLs relevant to population-wide variation in blood pressure. These QTLs are relevant not only to high individual cardiovascular risk (highest pressures) but also high population-attributable cardiovascular risk (average to high pressures). We thank Prof. John Hopper (Australian NHMRC Twin Registry), Dr. Graham Giles (Collaborative Cohort Study, Health 2000), the general practitioners, and research nurses for contributions to subject recruitment, Prof. Terry Speed for advice regarding linkage analyses, and the Australian Genome Research Facility for genotyping analyses. This work was supported by the Victorian Health Promotion Foundation. REFERENCES 1. Bahlo M and Broman KW. Identification and adjustment for genotyping errors in data on sibpairs when parental genotypes are unavailable (Abstract). Am J Hum Genet 65: 241, Daly MJ and Lander ES. The importance of being independent: sib pair analysis in diabetes. Nat Genet 14: , Deng AY, Dene H, and Rapp JP. Mapping of a quantitative trait locus for blood pressure on rat chromosome 2. J Clin Invest 94: , Deng AY, Dene H, Pravenec M, and Rapp JP. Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes. J Clin Invest 93: , Ellis JA, Stebbing M, and Harrap SB. Association of the human Y chromosome with high blood pressure in the general population. Hypertension 36: , Ely DL and Turner ME. Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome. Hypertension 16: , Harrap SB, Stebbing M, Hopper JL, Hoang HN, and Giles GG. Familial patterns of covariation for cardiovascular risk factors in adults: the Victorian Family Heart Study. Am J Epidemiol 152: , Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Soubrier F, Dubay C, Cartwright P, De Gouyon B, Julier C, Takahasi S, Vincent M, Ganten D, Georges M, and Lathrop GM. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353: , Hsueh WC, Mitchell BD, Schneider JL, Wagner MJ, Bell CJ, Nanthakumar E, and Shuldiner AR. QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31 34 in Old Order Amish. Circulation 101: , Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, and Corvol P. Molecular basis of human hypertension: role of angiotensinogen. Cell 71: , 1992.

7 BLOOD PRESSURE GENES Kruglyak L, Daly MJ, Reeve-Daly MP, and Lander E. Parametric and nonparametric linkage analyses: a unified approach. Am J Hum Genet 58: , Krushkal J, Ferrell R, Mockrin SC, Turner ST, Sing CF, and Boerwinkle E. Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation 99: , Lander E and Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11: , Lever AF and Harrap SB. Essential hypertension: a disorder of growth with origins in childhood? J Hypertens 10: , Levy D, DeStefano AL, Larson MG, O Donnell CJ, Lifton RP, Gavras G, Cupples LA, and Myers RH. Evidence of a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension 36: , Lifton RP. Genetic determinants of human hypertension. Proc Natl Acad Sci USA 92: , Lincoln SE and Lander ES. Systematic detection of errors in genetic linkage analysis. Genomics 14: , Perola M, Kainulainen K, Pajukanta P, Terwilliger JD, Hiekkalinna T, Ellonen P, Kaprio J, Koskenvuo M, Kontula K, and Peltonen L. Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings. J Hypertens 18: , Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, and Rao DC. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec family study. Circulation 102: , Sharma P, Fatibene J, Ferraro F, Jia HY, Monteith S, Brown C, Clayton D, O Shaughnessy K, and Brown MJ. A genome-wide search for susceptibility loci to human essential hypertension. Hypertension 35: , Watt GCM, Harrap SB, Foy CJW, Holton DW, Edwards HE, Davidson HR, Connor JM, Lever AF, and Fraser R. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four corners approach to the identification of genetic determinants of blood pressure. J Hypertens 10: , Wong ZYH, Stebbing M, Ellis JA, Lamantia A, and Harrap SB. Genetic linkage of the - and -subunits of the epithelial sodium channel with systolic blood pressure in the general population. Lancet 353: , Xu XP, Rogus JJ, Terwedow HA, Yang JH, Wang ZX, Chen CZ, Niu TH, Wang BY, Xu HQ, Weiss S, Schork NJ, and Fang ZA. An extreme-sib-pair genome scan for genes regulating blood pressure. Am J Hum Genet 64: , Zhu DL, Wang HY, Xiong MM, He X, Chu SL, Jin L, Wang GL, Yuan WT, Zhao GS, Boerwinkle E, and Huang W. Linkage of hypertension to chromosome 2q14-q23 in Chinese families. J Hypertens 19: 55 61, Downloaded from by on December 5, 2017

Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood pressure in a large, homogeneous study population

Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood pressure in a large, homogeneous study population (2003) 17, 555 559 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood

More information

Introduction to linkage and family based designs to study the genetic epidemiology of complex traits. Harold Snieder

Introduction to linkage and family based designs to study the genetic epidemiology of complex traits. Harold Snieder Introduction to linkage and family based designs to study the genetic epidemiology of complex traits Harold Snieder Overview of presentation Designs: population vs. family based Mendelian vs. complex diseases/traits

More information

Dan Koller, Ph.D. Medical and Molecular Genetics

Dan Koller, Ph.D. Medical and Molecular Genetics Design of Genetic Studies Dan Koller, Ph.D. Research Assistant Professor Medical and Molecular Genetics Genetics and Medicine Over the past decade, advances from genetics have permeated medicine Identification

More information

Human Chromosome 17 in Essential Hypertension

Human Chromosome 17 in Essential Hypertension Review Human Chromosome 17 in Essential Hypertension J. Knight, P. B. Munroe, J. C. Pembroke and M. J. Caulfield Clinical Pharmacology, The William Harvey Research Institute Bart s and The London Queen

More information

During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin,

During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin, ESM Methods Hyperinsulinemic-euglycemic clamp procedure During the hyperinsulinemic-euglycemic clamp [1], a priming dose of human insulin (Novolin, Clayton, NC) was followed by a constant rate (60 mu m

More information

Blood pressure QTL that differentiate Dahl salt-sensitive and spontaneously hypertensive rats

Blood pressure QTL that differentiate Dahl salt-sensitive and spontaneously hypertensive rats Physiol Genomics 3: 33 38, 2000. Blood pressure QTL that differentiate Dahl salt-sensitive and spontaneously hypertensive rats MICHAEL R. GARRETT, YASSER SAAD, HOWARD DENE, AND JOHN P. RAPP Department

More information

Genomewide Linkage of Forced Mid-Expiratory Flow in Chronic Obstructive Pulmonary Disease

Genomewide Linkage of Forced Mid-Expiratory Flow in Chronic Obstructive Pulmonary Disease ONLINE DATA SUPPLEMENT Genomewide Linkage of Forced Mid-Expiratory Flow in Chronic Obstructive Pulmonary Disease Dawn L. DeMeo, M.D., M.P.H.,Juan C. Celedón, M.D., Dr.P.H., Christoph Lange, John J. Reilly,

More information

Effects of Stratification in the Analysis of Affected-Sib-Pair Data: Benefits and Costs

Effects of Stratification in the Analysis of Affected-Sib-Pair Data: Benefits and Costs Am. J. Hum. Genet. 66:567 575, 2000 Effects of Stratification in the Analysis of Affected-Sib-Pair Data: Benefits and Costs Suzanne M. Leal and Jurg Ott Laboratory of Statistical Genetics, The Rockefeller

More information

A comparison of statistical methods for adjusting the treatment effects in genetic association studies of quantitative traits

A comparison of statistical methods for adjusting the treatment effects in genetic association studies of quantitative traits 34 1 Journal of the Korean Society of Health Information and Health Statistics Volume 34, Number 1, 2009, pp. 53 62 53 한경화 1), 임길섭 2), 박성하 3), 장양수 4), 송기준 2) 1), 2), 3), 4) A comparison of statistical

More information

Stat 531 Statistical Genetics I Homework 4

Stat 531 Statistical Genetics I Homework 4 Stat 531 Statistical Genetics I Homework 4 Erik Erhardt November 17, 2004 1 Duerr et al. report an association between a particular locus on chromosome 12, D12S1724, and in ammatory bowel disease (Am.

More information

MULTIFACTORIAL DISEASES. MG L-10 July 7 th 2014

MULTIFACTORIAL DISEASES. MG L-10 July 7 th 2014 MULTIFACTORIAL DISEASES MG L-10 July 7 th 2014 Genetic Diseases Unifactorial Chromosomal Multifactorial AD Numerical AR Structural X-linked Microdeletions Mitochondrial Spectrum of Alterations in DNA Sequence

More information

A hypertensive father, but not hypertensive mother, determines blood pressure in normotensive male offspring through body mass index

A hypertensive father, but not hypertensive mother, determines blood pressure in normotensive male offspring through body mass index Journal of Human Hypertension (1998) 12, 441 445 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE A hypertensive father, but not hypertensive

More information

Complex Multifactorial Genetic Diseases

Complex Multifactorial Genetic Diseases Complex Multifactorial Genetic Diseases Nicola J Camp, University of Utah, Utah, USA Aruna Bansal, University of Utah, Utah, USA Secondary article Article Contents. Introduction. Continuous Variation.

More information

Non-parametric methods for linkage analysis

Non-parametric methods for linkage analysis BIOSTT516 Statistical Methods in Genetic Epidemiology utumn 005 Non-parametric methods for linkage analysis To this point, we have discussed model-based linkage analyses. These require one to specify a

More information

Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene. McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S.

Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene. McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S. Genome-wide Association Analysis Applied to Asthma-Susceptibility Gene McCaw, Z., Wu, W., Hsiao, S., McKhann, A., Tracy, S. December 17, 2014 1 Introduction Asthma is a chronic respiratory disease affecting

More information

The Inheritance of Complex Traits

The Inheritance of Complex Traits The Inheritance of Complex Traits Differences Among Siblings Is due to both Genetic and Environmental Factors VIDEO: Designer Babies Traits Controlled by Two or More Genes Many phenotypes are influenced

More information

Estimating genetic variation within families

Estimating genetic variation within families Estimating genetic variation within families Peter M. Visscher Queensland Institute of Medical Research Brisbane, Australia peter.visscher@qimr.edu.au 1 Overview Estimation of genetic parameters Variation

More information

Genetics and Genomics in Medicine Chapter 8 Questions

Genetics and Genomics in Medicine Chapter 8 Questions Genetics and Genomics in Medicine Chapter 8 Questions Linkage Analysis Question Question 8.1 Affected members of the pedigree above have an autosomal dominant disorder, and cytogenetic analyses using conventional

More information

Multifactorial Inheritance. Prof. Dr. Nedime Serakinci

Multifactorial Inheritance. Prof. Dr. Nedime Serakinci Multifactorial Inheritance Prof. Dr. Nedime Serakinci GENETICS I. Importance of genetics. Genetic terminology. I. Mendelian Genetics, Mendel s Laws (Law of Segregation, Law of Independent Assortment).

More information

An Introduction to Quantitative Genetics I. Heather A Lawson Advanced Genetics Spring2018

An Introduction to Quantitative Genetics I. Heather A Lawson Advanced Genetics Spring2018 An Introduction to Quantitative Genetics I Heather A Lawson Advanced Genetics Spring2018 Outline What is Quantitative Genetics? Genotypic Values and Genetic Effects Heritability Linkage Disequilibrium

More information

In Australian twins participating in three different

In Australian twins participating in three different Heritability and Stability of Resting Blood Pressure in Australian Twins Jouke-Jan Hottenga, 1 John B. Whitfield, 2 Eco J. C. de Geus, 1 Dorret I. Boomsma, 1 and Nicholas G. Martin 2 1 Department of Biological

More information

A Unified Sampling Approach for Multipoint Analysis of Qualitative and Quantitative Traits in Sib Pairs

A Unified Sampling Approach for Multipoint Analysis of Qualitative and Quantitative Traits in Sib Pairs Am. J. Hum. Genet. 66:1631 1641, 000 A Unified Sampling Approach for Multipoint Analysis of Qualitative and Quantitative Traits in Sib Pairs Kung-Yee Liang, 1 Chiung-Yu Huang, 1 and Terri H. Beaty Departments

More information

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p Meenagh, G. K., McGibbon, D., Nixon, J., Wright, G. D., Doherty, M., & Hughes, A. (2005). Lack of support for

More information

Chapter 2. Linkage Analysis. JenniferH.BarrettandM.DawnTeare. Abstract. 1. Introduction

Chapter 2. Linkage Analysis. JenniferH.BarrettandM.DawnTeare. Abstract. 1. Introduction Chapter 2 Linkage Analysis JenniferH.BarrettandM.DawnTeare Abstract Linkage analysis is used to map genetic loci using observations on relatives. It can be applied to both major gene disorders (parametric

More information

Alcohol and nicotine use and dependence: Common genetic and other risk factors

Alcohol and nicotine use and dependence: Common genetic and other risk factors Washington University School of Medicine Digital Commons@Becker Presentations 2006: Alcohol and Tobacco Dependence: from Bench to Bedside 2006 Alcohol and nicotine use and dependence: Common genetic and

More information

breast cancer; relative risk; risk factor; standard deviation; strength of association

breast cancer; relative risk; risk factor; standard deviation; strength of association American Journal of Epidemiology The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:

More information

For more information about how to cite these materials visit

For more information about how to cite these materials visit Author(s): Kerby Shedden, Ph.D., 2010 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/

More information

Performing. linkage analysis using MERLIN

Performing. linkage analysis using MERLIN Performing linkage analysis using MERLIN David Duffy Queensland Institute of Medical Research Brisbane, Australia Overview MERLIN and associated programs Error checking Parametric linkage analysis Nonparametric

More information

Imaging Genetics: Heritability, Linkage & Association

Imaging Genetics: Heritability, Linkage & Association Imaging Genetics: Heritability, Linkage & Association David C. Glahn, PhD Olin Neuropsychiatry Research Center & Department of Psychiatry, Yale University July 17, 2011 Memory Activation & APOE ε4 Risk

More information

Nonparametric Linkage Analysis. Nonparametric Linkage Analysis

Nonparametric Linkage Analysis. Nonparametric Linkage Analysis Limitations of Parametric Linkage Analysis We previously discued parametric linkage analysis Genetic model for the disease must be specified: allele frequency parameters and penetrance parameters Lod scores

More information

Effects of High and Low Sodium Diet on Blood Pressure. and Heart Rate in Mice Lacking the Functional

Effects of High and Low Sodium Diet on Blood Pressure. and Heart Rate in Mice Lacking the Functional SHORT COMMUNICATION Effects of High and Low Sodium Diet on Blood Pressure and Heart Rate in Mice Lacking the Functional Grainyhead-like 1 Gene A. WALKOWSKA 1, M. PAWLAK 2, S. M. JANE 3,4, E. KOMPANOWSKA-

More information

Adoption, twin, and family studies document a significant

Adoption, twin, and family studies document a significant Identification of Hypertension-Related QTLs in African American Sib Pairs Theodore A. Kotchen, Ulrich Broeckel, Clarence E. Grim, Pavel Hamet, Howard Jacob, Mary L. Kaldunski, Jane Morley Kotchen, Nicholas

More information

Statistical Evaluation of Sibling Relationship

Statistical Evaluation of Sibling Relationship The Korean Communications in Statistics Vol. 14 No. 3, 2007, pp. 541 549 Statistical Evaluation of Sibling Relationship Jae Won Lee 1), Hye-Seung Lee 2), Hyo Jung Lee 3) and Juck-Joon Hwang 4) Abstract

More information

BLOOD PRESSURE RESPONSE TO COLD PRESSOR TEST IN SIBLINGS OF HYPERTENSIVES

BLOOD PRESSURE RESPONSE TO COLD PRESSOR TEST IN SIBLINGS OF HYPERTENSIVES Indian J Physiol Pharmacol 2003; 47 (4) : 453 458 BLOOD PRESSURE RESPONSE TO COLD PRESSOR TEST IN SIBLINGS OF HYPERTENSIVES R. K. RAJASHEKAR*, YERUVA NIVEDITHA AND SUMITABHA GHOSH Department of Physiology,

More information

Association between the CYP11B2 gene 344T>C polymorphism and coronary artery disease: a meta-analysis

Association between the CYP11B2 gene 344T>C polymorphism and coronary artery disease: a meta-analysis Association between the CYP11B2 gene 344T>C polymorphism and coronary artery disease: a meta-analysis Y. Liu, H.L. Liu, W. Han, S.J. Yu and J. Zhang Department of Cardiology, The General Hospital of the

More information

Validation Study Result Form

Validation Study Result Form Validation Study Result Form Please complete Section 1 to Section 5 of this form and return it to dabl Educational Trust with copies of the validation Study Ref. plots. In Section 3 to Section 5, complete

More information

Lecture 6: Linkage analysis in medical genetics

Lecture 6: Linkage analysis in medical genetics Lecture 6: Linkage analysis in medical genetics Magnus Dehli Vigeland NORBIS course, 8 th 12 th of January 2018, Oslo Approaches to genetic mapping of disease Multifactorial disease Monogenic disease Syke

More information

Autosomal Dominant Orthostatic Hypotensive Disorder Maps to Chromosome 18q

Autosomal Dominant Orthostatic Hypotensive Disorder Maps to Chromosome 18q Am. J. Hum. Genet. 63:1425 1430, 1998 Autosomal Dominant Orthostatic Hypotensive Disorder Maps to Chromosome 18q Anita L. DeStefano, 1,2 Clinton T. Baldwin, 3 Michael Burzstyn, 2,* Irene Gavras, 2 Diane

More information

I conducted an internship at the Texas Biomedical Research Institute in the

I conducted an internship at the Texas Biomedical Research Institute in the Ashley D. Falk ashleydfalk@gmail.com My Internship at Texas Biomedical Research Institute I conducted an internship at the Texas Biomedical Research Institute in the spring of 2013. In this report I will

More information

Interaction of Genes and the Environment

Interaction of Genes and the Environment Some Traits Are Controlled by Two or More Genes! Phenotypes can be discontinuous or continuous Interaction of Genes and the Environment Chapter 5! Discontinuous variation Phenotypes that fall into two

More information

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6 (2002) 10, 259 ± 265 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02 $25.00 www.nature.com/ejhg ARTICLE Sex stratification of an inflammatory bowel disease genome search shows male-specific

More information

ORIGINAL ARTICLE. Genomewide Linkage Analysis to Presbycusis in the Framingham Heart Study

ORIGINAL ARTICLE. Genomewide Linkage Analysis to Presbycusis in the Framingham Heart Study ORIGINAL ARTICLE Genomewide Linkage Analysis to Presbycusis in the Framingham Heart Study Anita L. DeStefano, PhD; George A. Gates, MD; Nancy Heard-Costa, PhD; Richard H. Myers, PhD; Clinton T. Baldwin,

More information

A Genome-Wide Scan for Carotid Artery Intima-Media Thickness The Mexican-American Coronary Artery Disease Family Study

A Genome-Wide Scan for Carotid Artery Intima-Media Thickness The Mexican-American Coronary Artery Disease Family Study A Genome-Wide Scan for Carotid Artery Intima-Media Thickness The Mexican-American Coronary Artery Disease Family Study Dai Wang, PhD; Huiying Yang, MD, PhD; Manuel J. Quiñones, MD; Isabel Bulnes-Enriquez,

More information

Mapping quantitative trait loci in humans: achievements and limitations

Mapping quantitative trait loci in humans: achievements and limitations Review series Mapping quantitative trait loci in humans: achievements and limitations Partha P. Majumder and Saurabh Ghosh Human Genetics Unit, Indian Statistical Institute, Kolkata, India Recent advances

More information

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part I: Methods and Power Analysis

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part I: Methods and Power Analysis Am. J. Hum. Genet. 73:17 33, 2003 Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part I: Methods and Power Analysis Douglas F. Levinson, 1 Matthew D. Levinson, 1 Ricardo Segurado, 2 and

More information

HRAS1 Rare Minisatellite Alleles and Breast Cancer in Australian Women Under Age Forty Years

HRAS1 Rare Minisatellite Alleles and Breast Cancer in Australian Women Under Age Forty Years HRAS1 Rare Minisatellite Alleles and Breast Cancer in Australian Women Under Age Forty Years Frank A. Firgaira, Ram Seshadri, Christopher R. E. McEvoy, Gillian S. Dite, Graham G. Giles, Margaret R. E.

More information

Combined Analysis of Hereditary Prostate Cancer Linkage to 1q24-25

Combined Analysis of Hereditary Prostate Cancer Linkage to 1q24-25 Am. J. Hum. Genet. 66:945 957, 000 Combined Analysis of Hereditary Prostate Cancer Linkage to 1q4-5: Results from 77 Hereditary Prostate Cancer Families from the International Consortium for Prostate Cancer

More information

Letters to the Editor

Letters to the Editor Am. J. Hum. Genet. 63:1552 1558, 1998 Letters to the Editor Am. J. Hum. Genet. 63:1552, 1998 Rett Syndrome: Confirmation of X-Linked Dominant Inheritance, and Localization of the Gene to Xq28 To the Editor:

More information

Genome - Wide Linkage Mapping

Genome - Wide Linkage Mapping Biological Sciences Initiative HHMI Genome - Wide Linkage Mapping Introduction This activity is based on the work of Dr. Christine Seidman et al that was published in Circulation, 1998, vol 97, pgs 2043-2048.

More information

Combined Linkage and Association in Mx. Hermine Maes Kate Morley Dorret Boomsma Nick Martin Meike Bartels

Combined Linkage and Association in Mx. Hermine Maes Kate Morley Dorret Boomsma Nick Martin Meike Bartels Combined Linkage and Association in Mx Hermine Maes Kate Morley Dorret Boomsma Nick Martin Meike Bartels Boulder 2009 Outline Intro to Genetic Epidemiology Progression to Linkage via Path Models Linkage

More information

Linkage Analyses at the Chromosome 1 Loci 1q24-25 (HPC1), 1q (PCAP), and 1p36 (CAPB) in Families with Hereditary Prostate Cancer

Linkage Analyses at the Chromosome 1 Loci 1q24-25 (HPC1), 1q (PCAP), and 1p36 (CAPB) in Families with Hereditary Prostate Cancer Am. J. Hum. Genet. 66:539 546, 2000 Linkage Analyses at the Chromosome 1 Loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in Families with Hereditary Prostate Cancer Rebecca Berry, 1,* Daniel J.

More information

Multifactorial Inheritance

Multifactorial Inheritance S e s s i o n 6 Medical Genetics Multifactorial Inheritance and Population Genetics J a v a d J a m s h i d i F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s, Novemb e r 2 0 1 7 Multifactorial

More information

A gene is a sequence of DNA that resides at a particular site on a chromosome the locus (plural loci). Genetic linkage of genes on a single

A gene is a sequence of DNA that resides at a particular site on a chromosome the locus (plural loci). Genetic linkage of genes on a single 8.3 A gene is a sequence of DNA that resides at a particular site on a chromosome the locus (plural loci). Genetic linkage of genes on a single chromosome can alter their pattern of inheritance from those

More information

Introduction to Genetics and Genomics

Introduction to Genetics and Genomics 2016 Introduction to enetics and enomics 3. ssociation Studies ggibson.gt@gmail.com http://www.cig.gatech.edu Outline eneral overview of association studies Sample results hree steps to WS: primary scan,

More information

Discontinuous Traits. Chapter 22. Quantitative Traits. Types of Quantitative Traits. Few, distinct phenotypes. Also called discrete characters

Discontinuous Traits. Chapter 22. Quantitative Traits. Types of Quantitative Traits. Few, distinct phenotypes. Also called discrete characters Discontinuous Traits Few, distinct phenotypes Chapter 22 Also called discrete characters Quantitative Genetics Examples: Pea shape, eye color in Drosophila, Flower color Quantitative Traits Phenotype is

More information

CS2220 Introduction to Computational Biology

CS2220 Introduction to Computational Biology CS2220 Introduction to Computational Biology WEEK 8: GENOME-WIDE ASSOCIATION STUDIES (GWAS) 1 Dr. Mengling FENG Institute for Infocomm Research Massachusetts Institute of Technology mfeng@mit.edu PLANS

More information

Mendelian & Complex Traits. Quantitative Imaging Genomics. Genetics Terminology 2. Genetics Terminology 1. Human Genome. Genetics Terminology 3

Mendelian & Complex Traits. Quantitative Imaging Genomics. Genetics Terminology 2. Genetics Terminology 1. Human Genome. Genetics Terminology 3 Mendelian & Complex Traits Quantitative Imaging Genomics David C. Glahn, PhD Olin Neuropsychiatry Research Center & Department of Psychiatry, Yale University July, 010 Mendelian Trait A trait influenced

More information

Complex Trait Genetics in Animal Models. Will Valdar Oxford University

Complex Trait Genetics in Animal Models. Will Valdar Oxford University Complex Trait Genetics in Animal Models Will Valdar Oxford University Mapping Genes for Quantitative Traits in Outbred Mice Will Valdar Oxford University What s so great about mice? Share ~99% of genes

More information

Interaction of six candidate genes in essential hypertension

Interaction of six candidate genes in essential hypertension Interaction of six candidate genes in essential hypertension D.C. Hu, X.L. Zhao, J.C. Shao, W. Wang, J. Qian, A.H. Chen, H.Q. Zhang, H. Guo, J. Jiang and H.Y. Li Department of Clinical Laboratory, The

More information

Chapter 5 INTERACTIONS OF GENES AND THE ENVIRONMENT

Chapter 5 INTERACTIONS OF GENES AND THE ENVIRONMENT Chapter 5 INTERACTIONS OF GENES AND THE ENVIRONMENT Chapter Summary Up to this point, the traits you have been studying have all been controlled by one pair of genes. However, many traits, including some

More information

Learning Abilities and Disabilities

Learning Abilities and Disabilities CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Learning Abilities and Disabilities Generalist Genes, Specialist Environments Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry,

More information

New Enhancements: GWAS Workflows with SVS

New Enhancements: GWAS Workflows with SVS New Enhancements: GWAS Workflows with SVS August 9 th, 2017 Gabe Rudy VP Product & Engineering 20 most promising Biotech Technology Providers Top 10 Analytics Solution Providers Hype Cycle for Life sciences

More information

The -adrenoceptor ( -AR) G s protein system has been

The -adrenoceptor ( -AR) G s protein system has been Association of GNAS1 Gene Variant With Hypertension Depending on Smoking Status Michiko Abe, Jun Nakura, Miyuki Yamamoto, Ji Jing Jin, Zhihong Wu, Yasuharu Tabara, Yoshikuni Yamamoto, Michiya Igase, Katsuhiko

More information

Alcohol consumption and blood pressure change: 5-year follow-up study of the association in normotensive workers

Alcohol consumption and blood pressure change: 5-year follow-up study of the association in normotensive workers (2001) 15, 367 372 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Alcohol consumption and blood pressure change: 5-year follow-up study of the

More information

Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population

Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population Author's response to reviews Title:Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population Authors: Jin-Kyu Park (cardiohy@gmail.com)

More information

Cardiovascular diseases identification of genomic markers Potential interest, limitations

Cardiovascular diseases identification of genomic markers Potential interest, limitations Cardiovascular diseases identification of genomic markers Potential interest, limitations Degenerative cardiovascular diseases Complexity of anatomical and clinical phenotypes (arterial remodeling, obstruction,

More information

GARRY R. CUTTING, MD PROFESSOR OF MEDICAL GENETICS DIRECTOR OF THE DNA DIAGNOSTIC LABORATORY THE JOHNS HOPKINS UNIVERSITY BALTIMORE, MARYLAND

GARRY R. CUTTING, MD PROFESSOR OF MEDICAL GENETICS DIRECTOR OF THE DNA DIAGNOSTIC LABORATORY THE JOHNS HOPKINS UNIVERSITY BALTIMORE, MARYLAND GARRY R. CUTTING, MD PROFESSOR OF MEDICAL GENETICS DIRECTOR OF THE DNA DIAGNOSTIC LABORATORY THE JOHNS HOPKINS UNIVERSITY BALTIMORE, MARYLAND MODIFIERS OF CYSTIC FIBROSIS LUNG FUNCTION MEASURES IN CF PATIENTS

More information

National Disease Research Interchange Annual Progress Report: 2010 Formula Grant

National Disease Research Interchange Annual Progress Report: 2010 Formula Grant National Disease Research Interchange Annual Progress Report: 2010 Formula Grant Reporting Period July 1, 2011 June 30, 2012 Formula Grant Overview The National Disease Research Interchange received $62,393

More information

Most studies have examined genetic and environmental effects in the variation of blood pressure in crosssectional

Most studies have examined genetic and environmental effects in the variation of blood pressure in crosssectional Original article 1543 Repeated blood pressure measurements in a sample of Swedish twins: heritabilities and associations with polymorphisms in the renin-angiotensin-aldosterone system Anastasia Iliadou

More information

Nomogram of the Relation of Brachial-Ankle Pulse Wave Velocity with Blood Pressure

Nomogram of the Relation of Brachial-Ankle Pulse Wave Velocity with Blood Pressure 801 Original Article Nomogram of the Relation of Brachial-Ankle Pulse Wave Velocity with Blood Pressure Akira YAMASHINA, Hirofumi TOMIYAMA, Tomio ARAI, Yutaka KOJI, Minoru YAMBE, Hiroaki MOTOBE, Zydem

More information

Mapping of genes causing dyslexia susceptibility Clyde Francks Wellcome Trust Centre for Human Genetics University of Oxford Trinity 2001

Mapping of genes causing dyslexia susceptibility Clyde Francks Wellcome Trust Centre for Human Genetics University of Oxford Trinity 2001 Mapping of genes causing dyslexia susceptibility Clyde Francks Wellcome Trust Centre for Human Genetics University of Oxford Trinity 2001 Thesis submitted for the degree of Doctor of Philosophy Mapping

More information

Publications (* denote senior corresponding author)

Publications (* denote senior corresponding author) Publications (* denote senior corresponding author) 1. Sha Q, Zhang K, * Zhang SL (2016) A nonparametric regression approach to control for population stratification in rare variant association studies.

More information

Validation Study Result Form

Validation Study Result Form Validation Study Result Form Please complete Section 1 to Section 3 of this form and return it to dabl Educational Trust with copies of the validation plots. The requirements for each of these sections

More information

Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2

Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2 (2003) 11, 835 839 & 2003 Nature Publishing Group All rights reserved 1018-4813/03 $25.00 www.nature.com/ejhg ARTICLE Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region

More information

Name: PS#: Biol 3301 Midterm 1 Spring 2012

Name: PS#: Biol 3301 Midterm 1 Spring 2012 Name: PS#: Biol 3301 Midterm 1 Spring 2012 Multiple Choice. Circle the single best answer. (4 pts each) 1. Which of the following changes in the DNA sequence of a gene will produce a new allele? a) base

More information

Quantitative genetics: traits controlled by alleles at many loci

Quantitative genetics: traits controlled by alleles at many loci Quantitative genetics: traits controlled by alleles at many loci Human phenotypic adaptations and diseases commonly involve the effects of many genes, each will small effect Quantitative genetics allows

More information

Introduction of Genome wide Complex Trait Analysis (GCTA) Presenter: Yue Ming Chen Location: Stat Gen Workshop Date: 6/7/2013

Introduction of Genome wide Complex Trait Analysis (GCTA) Presenter: Yue Ming Chen Location: Stat Gen Workshop Date: 6/7/2013 Introduction of Genome wide Complex Trait Analysis (GCTA) resenter: ue Ming Chen Location: Stat Gen Workshop Date: 6/7/013 Outline Brief review of quantitative genetics Overview of GCTA Ideas Main functions

More information

Genetics and Pharmacogenetics in Human Complex Disorders (Example of Bipolar Disorder)

Genetics and Pharmacogenetics in Human Complex Disorders (Example of Bipolar Disorder) Genetics and Pharmacogenetics in Human Complex Disorders (Example of Bipolar Disorder) September 14, 2012 Chun Xu M.D, M.Sc, Ph.D. Assistant professor Texas Tech University Health Sciences Center Paul

More information

Lecture 20. Disease Genetics

Lecture 20. Disease Genetics Lecture 20. Disease Genetics Michael Schatz April 12 2018 JHU 600.749: Applied Comparative Genomics Part 1: Pre-genome Era Sickle Cell Anaemia Sickle-cell anaemia (SCA) is an abnormality in the oxygen-carrying

More information

B-4.7 Summarize the chromosome theory of inheritance and relate that theory to Gregor Mendel s principles of genetics

B-4.7 Summarize the chromosome theory of inheritance and relate that theory to Gregor Mendel s principles of genetics B-4.7 Summarize the chromosome theory of inheritance and relate that theory to Gregor Mendel s principles of genetics The Chromosome theory of inheritance is a basic principle in biology that states genes

More information

Prevalence, awareness of hypertension in rural areas of Kurnool

Prevalence, awareness of hypertension in rural areas of Kurnool Original article: Prevalence, awareness of hypertension in rural areas of Kurnool Dr. Sudhakar Babu*, Dr.Aruna MS** *Associate Professor, Dept of Community Medicine, Vishwa Bharathi Medical College Kurnool,

More information

MOLECULAR EPIDEMIOLOGY Afiono Agung Prasetyo Faculty of Medicine Sebelas Maret University Indonesia

MOLECULAR EPIDEMIOLOGY Afiono Agung Prasetyo Faculty of Medicine Sebelas Maret University Indonesia MOLECULAR EPIDEMIOLOGY GENERAL EPIDEMIOLOGY General epidemiology is the scientific basis of public health Descriptive epidemiology: distribution of disease in populations Incidence and prevalence rates

More information

Adolescent Hypertension Roles of obesity and hyperuricemia. Daniel Landau, MD Pediatrics, Soroka University Medical Center

Adolescent Hypertension Roles of obesity and hyperuricemia. Daniel Landau, MD Pediatrics, Soroka University Medical Center Adolescent Hypertension Roles of obesity and hyperuricemia Daniel Landau, MD Pediatrics, Soroka University Medical Center Blood Pressure Tables BP standards based on sex, age, and height provide a precise

More information

Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension

Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension Human Molecular Genetics, 2006, Vol. 15, No. 8 1365 1374 doi:10.1093/hmg/ddl058 Advance Access published on March 16, 2006 Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension

More information

Received 5 April 2018; revised 31 July 2018; accepted 14 August 2018; published online 24 November 2018

Received 5 April 2018; revised 31 July 2018; accepted 14 August 2018; published online 24 November 2018 Journal of Genetics, Vol. 97, No. 5, December 2018, pp. 1413 1420 https://doi.org/10.1007/s12041-018-1040-7 Indian Academy of Sciences RESEARCH ARTICLE Quantitative trait loci that determine plasma insulin

More information

Chapter 4 INSIG2 Polymorphism and BMI in Indian Population

Chapter 4 INSIG2 Polymorphism and BMI in Indian Population Chapter 4 INSIG2 Polymorphism and BMI in Indian Population 4.1 INTRODUCTION Diseases like cardiovascular disorders (CVD) are emerging as major causes of death in India (Ghaffar A et. al., 2004). Various

More information

Supplementary Figures

Supplementary Figures Supplementary Figures Supplementary Fig 1. Comparison of sub-samples on the first two principal components of genetic variation. TheBritishsampleisplottedwithredpoints.The sub-samples of the diverse sample

More information

An Introduction to Quantitative Genetics

An Introduction to Quantitative Genetics An Introduction to Quantitative Genetics Mohammad Keramatipour MD, PhD Keramatipour@tums.ac.ir ac ir 1 Mendel s work Laws of inheritance Basic Concepts Applications Predicting outcome of crosses Phenotype

More information

Linkage of creatinine clearance to chromosome 10 in Utah pedifunction that can be detected while subjects are still healthy.

Linkage of creatinine clearance to chromosome 10 in Utah pedifunction that can be detected while subjects are still healthy. Kidney International, Vol. 62 (2002), pp. 1143 1148 Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the

More information

Research. A comparison of blood pressure measurement over a sleeved arm versus a bare arm. The measurement of blood pressure is one of the

Research. A comparison of blood pressure measurement over a sleeved arm versus a bare arm. The measurement of blood pressure is one of the A comparison of blood pressure measurement over a sleeved arm versus a bare arm Grace Ma MD, Norman Sabin MD, Martin Dawes MBBS MD @ See related article page 591 DOI:10.1503/cmaj.070975 Abstract Background:

More information

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia theoret read

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia theoret read Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia Simon E. Fisher 1 *, Clyde Francks 1 *, Angela J. Marlow 1, I. Laurence MacPhie 1, Dianne F. Newbury

More information

Within-family outliers: segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs

Within-family outliers: segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs (2008) 16, 516 524 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 ARTICLE www.nature.com/ejhg Within-family outliers: segregating alleles or environmental effects? A linkage analysis

More information

Polymorphic Variations in 5 HT2A, 5 HTT and DISC 1 in first episode schizophrenia patients

Polymorphic Variations in 5 HT2A, 5 HTT and DISC 1 in first episode schizophrenia patients PolymorphicVariationsin5 HT2A,5 HTTandDISC1infirst episodeschizophreniapatients L.MedinaGonzález,DepartmentofClinicalChemistry,RamónyCajalHospital,Madrid. PhD.MJArranz,SectionofClinicalNeuropharmacologyattheInstituteofPsychiatry,

More information

Pedigree Construction Notes

Pedigree Construction Notes Name Date Pedigree Construction Notes GO TO à Mendelian Inheritance (http://www.uic.edu/classes/bms/bms655/lesson3.html) When human geneticists first began to publish family studies, they used a variety

More information

Queensland scientists lead international study discovering Genes Behind Endometriosis

Queensland scientists lead international study discovering Genes Behind Endometriosis NEWS RELEASE Queensland Institute of Medical Research Friday August 19, 2005 Queensland scientists lead international study discovering Genes Behind Endometriosis A team of international scientists headed

More information

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q (2004) 12, 835 842 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

More information

Validation of the SEJOY BP-1307 upper arm blood pressure monitor for home. blood pressure monitoring according to the European Society of Hypertension

Validation of the SEJOY BP-1307 upper arm blood pressure monitor for home. blood pressure monitoring according to the European Society of Hypertension Validation of the SEJOY BP-1307 upper arm blood pressure monitor for home blood pressure monitoring according to the European Society of Hypertension International Protocol revision 2010 Short title: Validation

More information

Lecture 1 Mendelian Inheritance

Lecture 1 Mendelian Inheritance Genes Mendelian Inheritance Lecture 1 Mendelian Inheritance Jurg Ott Gregor Mendel, monk in a monastery in Brünn (now Brno in Czech Republic): Breeding experiments with the garden pea: Flower color and

More information

Interaction of Genes and the Environment

Interaction of Genes and the Environment Some Traits Are Controlled by Two or More Genes! Phenotypes can be discontinuous or continuous Interaction of Genes and the Environment Chapter 5! Discontinuous variation Phenotypes that fall into two

More information

Driving Question: What difference does it make if a gene is part of the X Chromosome?

Driving Question: What difference does it make if a gene is part of the X Chromosome? Genetics - X-linkage Teacher s Guide 1.0 Summary The X-Linkage Activity is the sixth core Genetics activity. This activity is comprised of three sections and designed to last one class period of approximately

More information