Alzheimer Disease and Complex Segregation Analysis p.1/29
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1 Alzheimer Disease and Complex Segregation Analysis Amanda Halladay Dalhousie University Alzheimer Disease and Complex Segregation Analysis p.1/29
2 Outline Background Information on Alzheimer Disease Alzheimer Disease and Complex Segregation Analysis p.2/29
3 Outline Background Information on Alzheimer Disease Complex Diseases Alzheimer Disease and Complex Segregation Analysis p.2/29
4 Outline Background Information on Alzheimer Disease Complex Diseases Complex Segregation Analysis Alzheimer Disease and Complex Segregation Analysis p.2/29
5 Outline Background Information on Alzheimer Disease Complex Diseases Complex Segregation Analysis Pros and Cons of CSA Alzheimer Disease and Complex Segregation Analysis p.2/29
6 Outline Background Information on Alzheimer Disease Complex Diseases Complex Segregation Analysis Pros and Cons of CSA Three Relevant Case Studies Alzheimer Disease and Complex Segregation Analysis p.2/29
7 Outline Background Information on Alzheimer Disease Complex Diseases Complex Segregation Analysis Pros and Cons of CSA Three Relevant Case Studies Comparisons and Conclusions Alzheimer Disease and Complex Segregation Analysis p.2/29
8 AD Background Degenerative brain disease Alzheimer Disease and Complex Segregation Analysis p.3/29
9 AD Background Degenerative brain disease Genetically complex and heterogenous Alzheimer Disease and Complex Segregation Analysis p.3/29
10 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes Alzheimer Disease and Complex Segregation Analysis p.3/29
11 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes 25% familial (EOFAD, LOFAD) Alzheimer Disease and Complex Segregation Analysis p.3/29
12 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes 25% familial (EOFAD, LOFAD) EOFAD caused by mutations in APP, PSEN1, and PSEN2 genes Alzheimer Disease and Complex Segregation Analysis p.3/29
13 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes 25% familial (EOFAD, LOFAD) EOFAD caused by mutations in APP, PSEN1, and PSEN2 genes LOFAD linked with APOE ɛ4 Alzheimer Disease and Complex Segregation Analysis p.3/29
14 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes 25% familial (EOFAD, LOFAD) EOFAD caused by mutations in APP, PSEN1, and PSEN2 genes LOFAD linked with APOE ɛ4 <1% chromosomal (trisomy 21) Alzheimer Disease and Complex Segregation Analysis p.3/29
15 AD Background Degenerative brain disease Genetically complex and heterogenous Three main causes 25% familial (EOFAD, LOFAD) EOFAD caused by mutations in APP, PSEN1, and PSEN2 genes LOFAD linked with APOE ɛ4 <1% chromosomal (trisomy 21) 75% genetic/environmental factors Alzheimer Disease and Complex Segregation Analysis p.3/29
16 Complex Diseases Not caused by a single gene Alzheimer Disease and Complex Segregation Analysis p.4/29
17 Complex Diseases Not caused by a single gene Mendelian linkage analysis not appropriate Alzheimer Disease and Complex Segregation Analysis p.4/29
18 Complex Diseases Not caused by a single gene Mendelian linkage analysis not appropriate Modeled using all factors, joint distributions, and joint effect on risk Alzheimer Disease and Complex Segregation Analysis p.4/29
19 Complex Diseases Not caused by a single gene Mendelian linkage analysis not appropriate Modeled using all factors, joint distributions, and joint effect on risk Approaches to linkage analysis Alzheimer Disease and Complex Segregation Analysis p.4/29
20 Complex Diseases Not caused by a single gene Mendelian linkage analysis not appropriate Modeled using all factors, joint distributions, and joint effect on risk Approaches to linkage analysis Non-parametric (model-free) Alzheimer Disease and Complex Segregation Analysis p.4/29
21 Complex Diseases Not caused by a single gene Mendelian linkage analysis not appropriate Modeled using all factors, joint distributions, and joint effect on risk Approaches to linkage analysis Non-parametric (model-free) Use parametric model as approximation (i.e. MC simulations) Alzheimer Disease and Complex Segregation Analysis p.4/29
22 Complex Segregation Analysis Evaluates transmission of a complex trait Alzheimer Disease and Complex Segregation Analysis p.5/29
23 Complex Segregation Analysis Evaluates transmission of a complex trait Tests models of varying degrees of generality Alzheimer Disease and Complex Segregation Analysis p.5/29
24 Complex Segregation Analysis Evaluates transmission of a complex trait Tests models of varying degrees of generality General model Alzheimer Disease and Complex Segregation Analysis p.5/29
25 Complex Segregation Analysis Evaluates transmission of a complex trait Tests models of varying degrees of generality General model Mendelian model (τ 1 = 1, τ 2 = 0.5, τ 3 = 0) Alzheimer Disease and Complex Segregation Analysis p.5/29
26 Complex Segregation Analysis Evaluates transmission of a complex trait Tests models of varying degrees of generality General model Mendelian model (τ 1 = 1, τ 2 = 0.5, τ 3 = 0) Environmental model (τ 1 = τ 2 = τ 3 ) Alzheimer Disease and Complex Segregation Analysis p.5/29
27 Complex Segregation Analysis Evaluates transmission of a complex trait Tests models of varying degrees of generality General model Mendelian model (τ 1 = 1, τ 2 = 0.5, τ 3 = 0) Environmental model (τ 1 = τ 2 = τ 3 ) Polygenic model Alzheimer Disease and Complex Segregation Analysis p.5/29
28 Complex Segregation Analysis Compare models with likelihood ratio test Alzheimer Disease and Complex Segregation Analysis p.6/29
29 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: Alzheimer Disease and Complex Segregation Analysis p.6/29
30 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities Alzheimer Disease and Complex Segregation Analysis p.6/29
31 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies Alzheimer Disease and Complex Segregation Analysis p.6/29
32 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances Alzheimer Disease and Complex Segregation Analysis p.6/29
33 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances variances within each genotype Alzheimer Disease and Complex Segregation Analysis p.6/29
34 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances variances within each genotype residual genetic correlations Alzheimer Disease and Complex Segregation Analysis p.6/29
35 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances variances within each genotype residual genetic correlations Uses of CSA: Alzheimer Disease and Complex Segregation Analysis p.6/29
36 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances variances within each genotype residual genetic correlations Uses of CSA: LOD-method linkage analysis Alzheimer Disease and Complex Segregation Analysis p.6/29
37 Complex Segregation Analysis Compare models with likelihood ratio test Estimates parameters such as: transmission probabilities allele frequencies genotype means/genotype penetrances variances within each genotype residual genetic correlations Uses of CSA: LOD-method linkage analysis Clinical applications Alzheimer Disease and Complex Segregation Analysis p.6/29
38 CSA- Ascertainment Proband method Alzheimer Disease and Complex Segregation Analysis p.7/29
39 CSA- Ascertainment Proband method Ascertainment correction (difficult!) Alzheimer Disease and Complex Segregation Analysis p.7/29
40 CSA- Ascertainment Proband method Ascertainment correction (difficult!) Current approaches Alzheimer Disease and Complex Segregation Analysis p.7/29
41 CSA- Ascertainment Proband method Ascertainment correction (difficult!) Current approaches explicit model of ascertainment Alzheimer Disease and Complex Segregation Analysis p.7/29
42 CSA- Ascertainment Proband method Ascertainment correction (difficult!) Current approaches explicit model of ascertainment condition likelihood of pedigrees of data relevant to ascertainment Alzheimer Disease and Complex Segregation Analysis p.7/29
43 CSA- Ascertainment Proband method Ascertainment correction (difficult!) Current approaches explicit model of ascertainment condition likelihood of pedigrees of data relevant to ascertainment POINTER computer program Alzheimer Disease and Complex Segregation Analysis p.7/29
44 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches Alzheimer Disease and Complex Segregation Analysis p.8/29
45 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment Alzheimer Disease and Complex Segregation Analysis p.8/29
46 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment The model: x = g + c + e, where Alzheimer Disease and Complex Segregation Analysis p.8/29
47 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment The model: x = g + c + e, where g denotes the joint, additive, unobservable, contributions of a major transmissible effects Alzheimer Disease and Complex Segregation Analysis p.8/29
48 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment The model: x = g + c + e, where g denotes the joint, additive, unobservable, contributions of a major transmissible effects c denotes a multifactorial transmissible component, and Alzheimer Disease and Complex Segregation Analysis p.8/29
49 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment The model: x = g + c + e, where g denotes the joint, additive, unobservable, contributions of a major transmissible effects c denotes a multifactorial transmissible component, and e denotes a nontransmitted environment Alzheimer Disease and Complex Segregation Analysis p.8/29
50 CSA- A Unified Model Bridges the gap between single-gene Mendelian genetics and classical biometrics approaches A general model of inheritance that results from the joint effects of a major locus, a polygenic component, and random environment The model: x = g + c + e, where g denotes the joint, additive, unobservable, contributions of a major transmissible effects c denotes a multifactorial transmissible component, and e denotes a nontransmitted environment g, c, and e are independent, c N(0, C), and g N(0, G) Alzheimer Disease and Complex Segregation Analysis p.8/29
51 CSA- Pros Reliable and robust Alzheimer Disease and Complex Segregation Analysis p.9/29
52 CSA- Pros Reliable and robust Applicable to any pedigree structure (don t need to break up complex pedigrees) Alzheimer Disease and Complex Segregation Analysis p.9/29
53 CSA- Pros Reliable and robust Applicable to any pedigree structure (don t need to break up complex pedigrees) Useful for both qualitative and quantitative traits Alzheimer Disease and Complex Segregation Analysis p.9/29
54 CSA- Pros Reliable and robust Applicable to any pedigree structure (don t need to break up complex pedigrees) Useful for both qualitative and quantitative traits Can consider complicated transmission patterns Alzheimer Disease and Complex Segregation Analysis p.9/29
55 CSA- Pros Reliable and robust Applicable to any pedigree structure (don t need to break up complex pedigrees) Useful for both qualitative and quantitative traits Can consider complicated transmission patterns Can consider environmental disturbances Alzheimer Disease and Complex Segregation Analysis p.9/29
56 CSA- Cons Large amount of specific data typically required Alzheimer Disease and Complex Segregation Analysis p.10/29
57 CSA- Cons Large amount of specific data typically required No reliable method to determine required sample size Alzheimer Disease and Complex Segregation Analysis p.10/29
58 CSA- Cons Large amount of specific data typically required No reliable method to determine required sample size Sample size limits ability to evaluate more complex models Alzheimer Disease and Complex Segregation Analysis p.10/29
59 CSA- Cons Large amount of specific data typically required No reliable method to determine required sample size Sample size limits ability to evaluate more complex models Ascertainment adjustment still needs development Alzheimer Disease and Complex Segregation Analysis p.10/29
60 CSA- Cons Large amount of specific data typically required No reliable method to determine required sample size Sample size limits ability to evaluate more complex models Ascertainment adjustment still needs development Inability to distinguish between effect of a single locus underlying trait and effects of 2 or more independently acting loci with similar transmission patterns Alzheimer Disease and Complex Segregation Analysis p.10/29
61 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Alzheimer Disease and Complex Segregation Analysis p.11/29
62 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Alzheimer Disease and Complex Segregation Analysis p.11/29
63 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Are patterns of transmission influenced by proband s APOE genotype? Alzheimer Disease and Complex Segregation Analysis p.11/29
64 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Are patterns of transmission influenced by proband s APOE genotype? Three Approaches Alzheimer Disease and Complex Segregation Analysis p.11/29
65 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Are patterns of transmission influenced by proband s APOE genotype? Three Approaches Logistic Regression Alzheimer Disease and Complex Segregation Analysis p.11/29
66 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Are patterns of transmission influenced by proband s APOE genotype? Three Approaches Logistic Regression Multiple Linear Regression Alzheimer Disease and Complex Segregation Analysis p.11/29
67 Case Study 1- Jarvik et al (1996) GOAL: Determine if stratification of AD cases by APOE genotype clarifies genetics basis of AD in a community-based sample. Does family history predict AD or age of onset when genotype known? Are patterns of transmission influenced by proband s APOE genotype? Three Approaches Logistic Regression Multiple Linear Regression Complex Segregation Analysis Alzheimer Disease and Complex Segregation Analysis p.11/29
68 Case Study 1- The Data Case Control Case Control No Mean age (SD) 79.7 (6.3) 79.1 (6.6) 79.4 (7.4) (6.8) Mean age at onset (SD) 76.7 (6.0) 76.6 (7.4) FamHx FamHx FHx Missing ɛ2ɛ ɛ2ɛ ɛ3ɛ ɛ3ɛ ɛ4ɛ APOE missing f(ɛ4) Alzheimer Disease and Complex Segregation Analysis p.12/29
69 Case Study 1- Summary of Results E F A S, E F, E S, E F A, F S, E S A, and E A significant in predicting AD via logistic regression Alzheimer Disease and Complex Segregation Analysis p.13/29
70 Case Study 1- Summary of Results E F A S, E F, E S, E F A, F S, E S A, and E A significant in predicting AD via logistic regression APOE genotype and family history deemed significant in prediction onset age of AD via multiple regression Alzheimer Disease and Complex Segregation Analysis p.13/29
71 Case Study 1- Summary of Results E F A S, E F, E S, E F A, F S, E S A, and E A significant in predicting AD via logistic regression APOE genotype and family history deemed significant in prediction onset age of AD via multiple regression General model showed best fit via CSA Alzheimer Disease and Complex Segregation Analysis p.13/29
72 Case Study 1- Summary of Results E F A S, E F, E S, E F A, F S, E S A, and E A significant in predicting AD via logistic regression APOE genotype and family history deemed significant in prediction onset age of AD via multiple regression General model showed best fit via CSA Alzheimer Disease and Complex Segregation Analysis p.13/29
73 Case Study 1- CSA Results Proband s APOE Genotype χ 2 for ɛ4+ χ 2 for ɛ4- df Without ascertainment correction, with residual correlations: Model 1: all τ s free Model 2: τ 1 = 1, τ 3 = Model 3: τ 1 = 1, τ 2 = 0.5, τ 3 = Model 4: τ 1 = τ 2 = τ Model 5: no major effect Model 6: correlations= With ascertainment correction, without residual correlations: Model 1: all τ s free Model 2: τ 1 = 1, τ 3 = Model 3: τ 1 = 1, τ 2 = 0.5, τ 3 = Model 4: τ 1 = τ 2 = τ Alzheimer Disease and Complex Segregation Analysis p.14/29
74 Case Study 2- Jimenez et al (2005) GOAL: To clinically, neuropathologically, and genetically analyze a cluster of related families with LOAD appearing in a genetic isolate. Alzheimer Disease and Complex Segregation Analysis p.15/29
75 Case Study 2- Jimenez et al (2005) GOAL: To clinically, neuropathologically, and genetically analyze a cluster of related families with LOAD appearing in a genetic isolate. The Data: Alzheimer Disease and Complex Segregation Analysis p.15/29
76 Case Study 2- Jimenez et al (2005) GOAL: To clinically, neuropathologically, and genetically analyze a cluster of related families with LOAD appearing in a genetic isolate. The Data: 10 families with autosomal dominant AD identified in small area in province of Guadalajara, Spain Alzheimer Disease and Complex Segregation Analysis p.15/29
77 Case Study 2- Jimenez et al (2005) GOAL: To clinically, neuropathologically, and genetically analyze a cluster of related families with LOAD appearing in a genetic isolate. The Data: 10 families with autosomal dominant AD identified in small area in province of Guadalajara, Spain Clustered into 3 extensive pedigress (P-a, P-b, I) Alzheimer Disease and Complex Segregation Analysis p.15/29
78 Case Study 2- Jimenez et al (2005) GOAL: To clinically, neuropathologically, and genetically analyze a cluster of related families with LOAD appearing in a genetic isolate. The Data: 10 families with autosomal dominant AD identified in small area in province of Guadalajara, Spain Clustered into 3 extensive pedigress (P-a, P-b, I) 12 affected and 16 unaffected individuals were examined clinically Alzheimer Disease and Complex Segregation Analysis p.15/29
79 Pedigree Alzheimer Disease and Complex Segregation Analysis p.16/29
80 Case Study 2- CSA CSA was performed to determine: a genetic basis, the best model of transmission, and the relative genetic and environmental effects Alzheimer Disease and Complex Segregation Analysis p.17/29
81 Case Study 2- CSA CSA was performed to determine: a genetic basis, the best model of transmission, and the relative genetic and environmental effects Used POINTER software (unified model) Alzheimer Disease and Complex Segregation Analysis p.17/29
82 Case Study 2- CSA CSA was performed to determine: a genetic basis, the best model of transmission, and the relative genetic and environmental effects Used POINTER software (unified model) CSA compared 10 models using likelihood ratio tests Alzheimer Disease and Complex Segregation Analysis p.17/29
83 Case Study 2- CSA CSA was performed to determine: a genetic basis, the best model of transmission, and the relative genetic and environmental effects Used POINTER software (unified model) CSA compared 10 models using likelihood ratio tests The best model found via CSA: major (dominant) gene effect model Alzheimer Disease and Complex Segregation Analysis p.17/29
84 Case Study 2- CSA Results No transmission d t q H Z t1 t2 t3 2 ln (L) + C 1 Sporadic (q = H = 0) (0) (0) (0) (0) (1) Multifactorial 2 No cohort effect (0) (0) (0) 0.64 (1) Major locus 3 Dominant (1) (0) (1) (1) (0.5) (0) Co-dominant (0.5) (0) (1) (1) (0.5) (0) Recessive (0) (0) (1) (1) (0.5) (0) d not restricted (0) (1) (1) (0.5) (0) Mixed model 7 Dominant (1) (1) (1) (0.5) (0) Co-dominant (0.5) (1) (1) (0.5) (0) Recessive (0) (1) (1) (0.5) (0) No major gene effect 10 t1 = t2 = t (1) Alzheimer 0.97 Disease 0.97 and Complex 0.97 Segregation Analysis p.18/29
85 Case Study 2- More CSA Results Models Compared χ 2 P-value df 1, < , < , , , , < , < Alzheimer Disease and Complex Segregation Analysis p.19/29
86 Case Study 2- Results Summary The best model was the major (dominant) gene effect model contrast to usual LOAD Alzheimer Disease and Complex Segregation Analysis p.20/29
87 Case Study 2- Results Summary The best model was the major (dominant) gene effect model contrast to usual LOAD Suspect a new gene could be located within these kindred Alzheimer Disease and Complex Segregation Analysis p.20/29
88 Case Study 3- Rao et al (1996) GOAL: To derive AD disease transmission models that account for influences of APOE genotype and gender. Alzheimer Disease and Complex Segregation Analysis p.21/29
89 Case Study 3- Rao et al (1996) GOAL: To derive AD disease transmission models that account for influences of APOE genotype and gender. The Data: Alzheimer Disease and Complex Segregation Analysis p.21/29
90 Case Study 3- Rao et al (1996) GOAL: To derive AD disease transmission models that account for influences of APOE genotype and gender. The Data: 636 nuclear families: 84 probands met definite AD criteria and 552 met probable AD criteria Alzheimer Disease and Complex Segregation Analysis p.21/29
91 Case Study 3- Rao et al (1996) GOAL: To derive AD disease transmission models that account for influences of APOE genotype and gender. The Data: 636 nuclear families: 84 probands met definite AD criteria and 552 met probable AD criteria Segregation analysis performed via logistic regression (age at onset) and CSA (stratified samples) Alzheimer Disease and Complex Segregation Analysis p.21/29
92 Case Study 3- Rao et al (1996) GOAL: To derive AD disease transmission models that account for influences of APOE genotype and gender. The Data: 636 nuclear families: 84 probands met definite AD criteria and 552 met probable AD criteria Segregation analysis performed via logistic regression (age at onset) and CSA (stratified samples) Several models fit to the data: dominant, recessive, additive, arbitrary major gene, no major gene, sporadic, random-environmental, and two general transmission models Alzheimer Disease and Complex Segregation Analysis p.21/29
93 Case Study 3- Table 1 Alzheimer Disease and Complex Segregation Analysis p.22/29
94 Case Study 3- Results AD transmission differs significantly between families in the two groups (with ɛ4 allele and without ɛ4 allele) Alzheimer Disease and Complex Segregation Analysis p.23/29
95 Case Study 3- Results AD transmission differs significantly between families in the two groups (with ɛ4 allele and without ɛ4 allele) Transmission in group with ɛ4 allele fit a dominance inheritance model Alzheimer Disease and Complex Segregation Analysis p.23/29
96 Case Study 3- Results AD transmission differs significantly between families in the two groups (with ɛ4 allele and without ɛ4 allele) Transmission in group with ɛ4 allele fit a dominance inheritance model Both recessive and dominant models equally likely for group without ɛ4 allele Alzheimer Disease and Complex Segregation Analysis p.23/29
97 Case Study 3- Results AD transmission differs significantly between families in the two groups (with ɛ4 allele and without ɛ4 allele) Transmission in group with ɛ4 allele fit a dominance inheritance model Both recessive and dominant models equally likely for group without ɛ4 allele Separation of families into ɛ4 and non-ɛ4 groups gave better fit than total group of families for every model tested Alzheimer Disease and Complex Segregation Analysis p.23/29
98 Case Study 3- Table 2 Alzheimer Disease and Complex Segregation Analysis p.24/29
99 Case Study 3- Table 3 Alzheimer Disease and Complex Segregation Analysis p.25/29
100 Case Study 3- Table 4 Alzheimer Disease and Complex Segregation Analysis p.26/29
101 Summary First Study: Alzheimer Disease and Complex Segregation Analysis p.27/29
102 Summary First Study: Case/Control Study of 237 probands Alzheimer Disease and Complex Segregation Analysis p.27/29
103 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Alzheimer Disease and Complex Segregation Analysis p.27/29
104 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Alzheimer Disease and Complex Segregation Analysis p.27/29
105 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Evidence implying a new gene linked to AD was present in these families Alzheimer Disease and Complex Segregation Analysis p.27/29
106 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Evidence implying a new gene linked to AD was present in these families Presence of APOE ɛ4 allele was associated with an increased risk of dementia, but not to an earlier age of onset Alzheimer Disease and Complex Segregation Analysis p.27/29
107 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Evidence implying a new gene linked to AD was present in these families Presence of APOE ɛ4 allele was associated with an increased risk of dementia, but not to an earlier age of onset Third Study: Alzheimer Disease and Complex Segregation Analysis p.27/29
108 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Evidence implying a new gene linked to AD was present in these families Presence of APOE ɛ4 allele was associated with an increased risk of dementia, but not to an earlier age of onset Third Study: In total group, the general/unrestricted model had best fit Alzheimer Disease and Complex Segregation Analysis p.27/29
109 Summary First Study: Case/Control Study of 237 probands The general model was the best fit which may imply that a more complex model would be better suited Second Study Evidence implying a new gene linked to AD was present in these families Presence of APOE ɛ4 allele was associated with an increased risk of dementia, but not to an earlier age of onset Third Study: In total group, the general/unrestricted model had best fit When broken into with ɛ4 and without ɛ4 groups, dominant inheritance shown in with ɛ4 group and a possible major gene in the without ɛ4 group Alzheimer Disease and Complex Segregation Analysis p.27/29
110 Conclusions All studies indicated possibility of a new gene (other than ɛ4) in the inheritance model of AD Alzheimer Disease and Complex Segregation Analysis p.28/29
111 Conclusions All studies indicated possibility of a new gene (other than ɛ4) in the inheritance model of AD APOE genotype (particularly ɛ4) allele shown to play important factor in the risk of AD Alzheimer Disease and Complex Segregation Analysis p.28/29
112 References Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., & Tanzi, R.E. (2007). Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genetics, 39, 1. Jarvik, G. Seattle (1998). Complex Segregation Analyses: Uses and Limitations Jimenez-Escrig, A., Gomez-tortosa, E., Baron, M., Rabano, A., Arcos-Burgos, M., Palacios, L.G., Yusta, A., Anta, P., Perez, I., Hierro, M., Munoz, D.G., & Barquero, S. (2005). A multigenerational pedigree of late-onset Alzheimer s disease implies new genetic causes. Brain, 128, Lalouel, J.M., Rao, D.C., Morton, N.E., & Elston, R.C. (1983). A Unified Model for Complex Segregation Analysis. American Journal of Human Genetics 35: Morton, N.E., Yee, S., & Lew, R. (1971). Complex Segregation Analysis. American Society of Human Genetics. Rao, V.S., Cupples, L.A., van Duijn, C.M., Kurz, A., Green, R.C., Chui, H., Duara, R., Auerbach, S.A., Volicer, L., Wells, J., van Broeckhoven, C., Growdon, J.H., Haines, J.L., & Farrer, L.A. (1996). Evidence for Major Gene Inheritance of Alzheimer Disease in Families of Patients With and Without Apolipoprotein E e4. American Journal of Human Genetics, 59: Sham, Pak. Statistics In Human Genetics, New York: John Wiley & Sons, Alzheimer Disease and Complex Segregation Analysis p.29/29
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