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

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1 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 by a single gene producing a clear pattern of dominant or recessive inheritance within families. Examples: cystic fibrosis, sickle cell anemia, hemophilia Complex Trait A trait influenced by multiple genes and their interactions with each other and with the environment. Examples: autism, schizophrenia, Alzheimer s, brain anatomy, BOLD signal Genetics Terminology 1 Genetics Terminology Quantitative Trait Locus (QTL), a location, usually a chromosomal region, implicated as containing one or more genes that influence a phenotype of interest Quantitative Trait Nucleotide (QTN), a specific sequence variation that has been implicated as having a functional effect on a phenotype of interest A QTL may contain multiple QTNs Chromosome: a single long string of DNA, humans have two copies of each chromosome (diploid), one from mom, one from dad Autosome: None sex chromosome ( in humans) Sex chromosome: X or Y chromosome, females have X, males have 1X and 1Y Mitochondrial DNA: non-nuclear DNA, inherited only from the mother Human Genome Genetics Terminology 3 3 Chromosomes ~0-5,000 genes ~3 billion base pairs Gene: a unit of DNA that codes for a protein (but the term may be used to include both coding and non-coding elements) Locus: location, sometimes used interchangably with gene Allele: the specific variant you have at a particular site in the genome, the possible variants at a locus

2 Genetics Terminology 4 Loci, Alleles, Genotypes, Genotype: the combination of alleles on the two chromosomes of an individual Haplotype: the alleles at different loci being carried together on the same chromosome Phenotype: the trait of interest, some measurable property of the individual Examples: neuroanatomy, neurophysiology, schizophrenia, bipolar disorder, Alzheimer s A 1 Two loci: letter locus & number locus Each locus has two alleles: A or B, 1 or The genotype at the letter locus is AB The haplotype on the first chromosome shown is A1 B Within A Gene Exon: specifies the mrna, which is translated into the series of amino acids in the protein, coding sequence Intron: non-coding, intravening sequence Splice site: the juncture between an exon & an intron Promoter, enhancer: regulatory element (usually non-coding), controls time, place, amount of transcription Functional & physical unit of heredity passed from parent to offspring (pieces of DNA) Typically contain information to make a specific protein Composed of nucleotides, sequence of four organic bases (Adenine, Guanine, Cytocine, and Thyamine) Matching nucleotides on the complimentary DNA strands form a base-pair The Gene A Small Gene: FVII gene (~15 kb) How to do Genetics -33 ± 10bp -401 G/T -1 T/C -40 G/A 73 G/A H115H A94V A/G R353Q IVS 7 S333S G/A Question What do you want to know? -668 A/C -316 C/T -68 A/G 1a 1b C/A T/C 60 A/G G/A A/G G/C 3.94 G/A 364 G/A T/A T/G A/G C/T 7.79 G/A 3.43 G/T 698 T/C 705 G/A 710 C/G bp 799 T/C 806 G/A 811 C/G 833T/C 945 G/A 3.98 G/A G/A G/A G/T 6.45 G/T T G/A T/C 9.79 G/A C/T G/A del AG ins AA Sample Who do you need to study? Method How will you use your data?

3 Questions for the Study of 1) Is this trait influenced by genetic factors? How strong are these genetic influences? ) Which traits are influenced by the same genes? 3) Where are the genes that influence a trait? 4) What are the specific genes that influence the trait? 5) What specific genetic variants influence the trait and how do they interact with each other and with the environment? Six Types of Samples for Genetics 1. Adoptees: separating the effects of genes and family environment. Unrelated individuals: association only, estimation of effect size after variants are identified 3. Parent-child triads: association in the presence of linkage (transmission disequilibrium test), heritability/relative risk 4. Twins: heritability, relative risk, genetic correlations, linkage, association 5. Relative pairs: heritability, relative risk, genetic correlations, linkage, association 6. Pedigrees: heritability, relative risk, genetic correlations, linkage, association Subject Ascertainment Strategies Question 1: Heritability 1. By phenotype: if you re studying a rare disease, you must ascertain on phenotype. This is also necessary for some study designs (TDT, case/control).. Randomly: if you re studying a common disease, you ll find it in a random sample. If you re interested in multiple traits, ascertaining on one improves power only for that one. May also want to study normal variation. 3. Ascertainment also depends on (and limits) method of analysis TDT, affected relative pair linkage. Is this trait influenced by genetic factors? How strong are these genetic influences? Defining Heritability Variance Decomposition!"#"$% &#'()"*+#,'-.#/"#0 13-"4*+#,'-.#/"#0 Phenotype (P) = Genotype (G) + Environment (E)! µ µ= ^ "x i / n ^! ^ = "(x - µ) / n Almasy & Blangero, Am J Hum Genet, 1998! p =! g +! e! g =! a +! d! e =! c +! eu! p = total phenotypic! g = genetic! e = environmental! a = additive genetic! d = dominance

4 Broad-Sense Heritability (H ) Decomposing Genetic Effects All possible genetic contributions allelic variation (additive variance) dominance variation, epistatic (multi-genic) interactions, maternal and paternal effects H =! g! p! =! +! g a d AA AB BB -a 0 d +a Defining Dominance Estimating Additive & Dominate AA AB BB -a 0 +a If the heterozygote is half way between the two homozygotes, there s a dose-response effect, d is zero, and there is no dominance. V A = pq[a + d(q-p)] V D = (pqd) Narrow-Sense Heritability (h ) Conceptualizing Heritability Heritability (h ): the proportion of the phenotypic variance in a trait attributable to the additive effects of genes. h =! a! p Heritability estimates vary between 0 and 1 0, genetic factors do not influence trait variance 1, trait variance is completely under genetic control If h =0.5, then 50% of phenotypic variation is due to genetic variation. Not that the trait is 50% caused by genetics Stronger heritability does not imply simple genetics

5 Estimating Heritability with Twins Falconer s Method h =*(r MZ -r DZ ) r MZ = correlation between monozygotic co-twins r DZ = correlation between dizygotic co-twins Estimating Heritability with Twins Monozygotic (identical): V A +V D Dizygotic (fraternal): 1/ V A + 1/4 V D x Difference = V A + 3/ V D! h Assuming that shared environmental effects are equal for both types of twins. Twin Concordances Limitations of Twins 5)$6/ 1%'7.8-"#'3 9'8.:3-*;'6.-4"- 5#.-"<'3 5;=; >3#'%*;'6.-4"- ;"8-"66'.# >?1;!5; 1.%'3:*>.@'3 AB;!"#$%&'$($%) Common Environment Unless Raised Apart Twins reared apart are difficult to find Common prenatal environment; intrauterine competition Mother may be physically stressed Twin samples are fundamentally less powerful for QTL localization Variance Component Approach Modeling the Phenotype: p= µ + "# i x i + a+ d+e µ Population mean # Regression coefficients x Scaled covariates a Additive genetic effects d Dominance genetic effects e Random environmental effects Variance Component Approach $ = %! a + & 7! d + "! e # coefficient of relationship between individuals $ probability that individuals share both alleles IBD " Kronecker function

6 Defining Mendelian Relationships Simple Kinship Matrix Relatives Covariance Heritability Parent-child 1/V A b = 1/ h Half siblings 1/4V A r = 1/4 h Full siblings 1/V A + 1/4V A r! 1/ h Cousins 1/8V A r = 1/8 h ignoring interactions and shared environmental effects Dad 1 Mom 3 D M 1 3 D 1 0 % % % M 0 1 % % % 1 % % 1 % % % % % 1 % 3 % % % % 1 Kinship Matrix Limitations of Heritability Estimates % % % % 4 % % 0 1 & 5 0 % % & 1 1. Heritability is a population level parameter, summarizing the strength of genetic influences on variation in a trait among members of the population. It doesn t tell you anything about particular individuals.. Heritability is an aggregate of the effects of multiple genes. It tells you nothing about how many genes influence a phenotype. A high heritability is not necessarily better if it is due to many, many genes. Relative Risk Heritable vs. Familial The risk to a relative of an affected individual as compared to a randomly chosen member of the population, '. 1 - ( A trait can be familial without being heritable. Genes are not the only thing shared by members of a family (e.g. diet, exercise, environmental exposures, etc). Nuclear families vs. extended pedigrees Adoption studies

7 Heritability of Volume & Gryi Bartely et al., Brain, MZ / 9 DZ pairs Gray-Matter Thickness Heritability Kremen et al., NeuroImage, MZ / 9 DZ pairs Vertex-Wide Cortical Thickness Winkler et al., Unpublished 76 family members Gray-Matter Thickness Heritability Thompson et al., Nat Neuro, MZ / 10 DZ pairs Cortical Thickness & Surface Area Winkler et al., NeuroImage, family members Superior Occipitofrontal Fascicle Hulshoff Pol et al. J. Neurosci, MZ / 58 DZ pairs / 34 Sibs

8 White-Matter Tracts (DTI) h White-Matter Hyperintensity h Total Cranial: 0.91 Brain Parenchyma: 0.9 WMH: 0.73 Kochunov et al., NeuroImage, family members White-Matter Hyperintensity h 74 MZ / 71 DZ pairs Task Based fmri Heritability Dorsal anterior cingulate cortex Conflict Processing h=0.38 Whole-brain WMH: 0.7 Subcortical WMH: 0.66 Ependymal WMH: 0.73 Kochunov et al., Stroke, 009 Carmelli et al., Stroke, family members Task Based fmri Heritability Matthews et al., NeuroImage, MZ / 10 DZ pairs Resting State fmri Heritability h= 0.44 Koten et al., Science, MZ pairs / 10 sibs Glahn et al., Proc Nat Sci USA, family members

9 Heritability Conclusions Question : Pleiotropy We ve got heritability!! Which traits are influenced by the same genes? Levels of Pleiotropy Genetic Correlation (Pleiotropy) No Pleiotropy Trait 1 Trait Genetic correlation () g ): a measure of the overlap in genetic effects between traits. Partial Pleiotropy Trait 1 Trait ) g varies from -1 to 1 Full Pleiotropy Trait 1 Trait 0 = no pleiotropy; -1 or 1 = complete pleiotropy Estimating Pleiotropy Cortical Thickness & Surface Area ) p = ) g '(h 1 h ) +) e '((1-h 1 )(1-h )) h 1 and h are the heritabilities of traits 1 and Schmitt et al., Cerebral Cortex, MZ / 47 DZ / 8 others Winkler et al., NeuroImage, family members

10 White-Matter Hyperintensity & Cortical Thinning & IQ WMH - Executive Function ) g = 0.70 WMH - Mini-Mental State Exam ) g = 1.0 Carmelli et al., Neurobiol Ageing, MZ / 70 DZ pairs ) g = 1.0/1.0 ) g = 1.0/0.7 Brans et al., J Neurosci, MZ / 84 DZ pairs White Matter Tracts & Pleiotropy Conclusions Superior longitudinal fasciculus Spatial DRT: ) g = Karlsgodt et al., J Neurosci, family members Coffee Break