Published on August 6, 2007
Sex differences in disease predisposition: Sex differences in disease predisposition Nancy L. Pedersen Dept. of Medical Epidemiology and Biostatistics Karolinska Institutet and Dept. of Psychology University of Southern California Outline: Outline Differences in prevalences and variance components Neuropsychiatric outcomes Alcohol dependence Depression Chronic fatigue Cognitive abilities and dementia Parkinson’s Sex differences in association studies Linkage studies Differences in levels or prevalences: Differences in levels or prevalences Somatic traits (quantitative) Height, chest circumference BMI HDL cholesterol Blood pressure Somatic disorders Asthma Type 2 diabetes Cardiovascular disease Interaction with age Autoimmune disorders Osteoporosis Differences in Prevalences – Neuropsychiatric Outcomes: Differences in Prevalences – Neuropsychiatric Outcomes Alcohol dependence andamp; abuse Autism Major depression Chronic fatigue, Chronic widespread pain Spatial abilities Alzheimer’s disease Survival? Parkinson’s disease Differences in prevalences…: Differences in prevalences… Are like means…. Don’t necessarily imply differences in genetic variance (heritability) Heritability focuses on within group variance Paths to finding different heritabilities: Paths to finding different heritabilities Like sexed twin pairs Compare h2 in males and females separately α : MZ = 1, DZ = .5 Sex limitation: Sex limitation Include opposite sex pairs γ OSZ correlation Patterns of Twin Pair Similarity and Genetic Correlations: Quantitative Sex Differences : 0 Patterns of Twin Pair Similarity and Genetic Correlations: Quantitative Sex Differences ♀ h2 andgt; ♂ h2 Patterns of Twin Pair Similarity and Genetic Correlations: Sex modified gene expression: 0 Patterns of Twin Pair Similarity and Genetic Correlations: Sex modified gene expression Twin Pair Similarity and Estimated Male-Female Genetic Correlations for Alcoholism: Twin Pair Similarity and Estimated Male-Female Genetic Correlations for Alcoholism Prescott et al 1999, Alcohol Clin Exp Res No quantitative differences i.e., h2 equal But only partially overlapping, qualtitative differences Major Depression: Major Depression Prevalence Sweden: (N=42,161 indiv) females 25% males, 13% Major Depression: Major Depression Kendler et al. (1999) Virginia Major Depression: Major Depression Genetic Correlation ?? Low power Kendler et al. (1999) Virginia Bierut et al. (1999) Australia Major Depression: Major Depression Kendler et al. (2005) Am J Psychiatry Genetic Correlation .55 Kendler et al. (2001) Psychol Med Virginia Major Depression: Major Depression Gen Corr .63 Kendler et al. (2005) Am J Psychiatry Gen Corr .55 Kendler et al. (2001) Psychol Med Virginia Sweden Mechanisms?: Mechanisms? Different social factors / exposures of etiologic relevance Evoke distinct genetically-based variation Hormonal influences Early development (perinatal) Variable hormonal environment (menstrual cycle) Elicit distinct genetic expression Different sets of genes influencing different phenotypes Alcoholism in men – antisocial subtype Related to genes for externalizing behavior In females, more related to depressive or anxiety symptoms Comorbidity: common liabilities or sex-specific expression?: Comorbidity: common liabilities or sex-specific expression? Prescott et al. (2000) Arch Gen Psychiat Chronic Fatigue: Chronic Fatigue Chronic Fatigue - prevalences: Chronic Fatigue - prevalences Chronic Fatigue - heritabilities: Chronic Fatigue - heritabilities Increasing degree of severity Sullivan et al. (2005) Psychol Med Cognitive abilities: Cognitive abilities Two of eleven cognitive measures: sex differences in rates of decline: Two of eleven cognitive measures: sex differences in rates of decline Finkel et al (2006) ANC Slide23: NO! Alzheimer disease: Alzheimer disease Gatz et al. (2006) Arch Gen Psychiatry Alzheimer disease Parkinsonism: Alzheimer disease Parkinsonism No differences in prevalence After controlling for age!!! Indication of shared env in women h2 = .45, c2 = .36 Men: h2 = .58, c2 = .07 Genetic correlation = 1 No sign sex diff in heritability h2 = .79 No differences in prevalence Regardless of age (0.5%) Significant shared env in men and women Women: c2 = .18 Men: c2 = .13 Genetic correlation = 1 Sign sex diff in heritability Women: h2 = .22 Men: h2 = .13 Gatz et al. (2006) Arch Gen Psychiatry Wirdefeldt et al. (2004) Neurology Patterns in neuropsychiatric disorders?: Patterns in neuropsychiatric disorders? Substance abuse Prev differences Same heritabilities Partial overlap in genes Depression Prev differences Different heritabilites Partial overlap in genes Chronic Fatigue Prev differences ? Same heritabilites and genes Cognitive abilities and decline Few differences No differences in heritabilities Same genes Alzheimer disease Prevalence differences due to age Same heritability Same genes Parkinsonism NO prev differences Differences in heritability Same genes Patterns in neuropsychiatric disorders?: Patterns in neuropsychiatric disorders? Phenotypic specific patterns Understanding differences important for understanding mechanisms ApoE, hormones and Alzheimers Consensus: 'Strategies to identify predisposing genes may benefit from taking into account potential sex specific effects' Slide28: Consequences for Linkage and Association? Association analyses: Depressive symptoms in elderly: Association analyses: Depressive symptoms in elderly h2 greater in women, association stronger in men Accounts for more of genetic variance in men? Jansson et al. (2003) Am J Med Gen Other sex dependent genetic associations: Other sex dependent genetic associations β2adrenoceptor and asthma: OR♂ andgt; OR♀ Santillan et al (2003) J Allergy Clin Immunol DISC1 and Schizophrenia Hennah et al (2003) Hum Mol Genet MMP3 promotor in men and celiac disease Mora et al (2005) Hum Immunol MTHFR assoc with lung cancer in women Shi et al (2005) Cancer Epidemiol Biomarkers Prev Slide31: Consequences for linkage studiesWeiss et al (2006) Nature Genetics: Consequences for linkage studies Weiss et al (2006) Nature Genetics Sex-specific genetic architecture of quantitative traits in humans Mean differences for 11 of 17 quantitative traits HDL-c, TG, DBP, SBP, BMI, Ht, FEV1, Eos, IgE, % Lymph, Serotonin Heritability differences or sex interactions for 5 of 17 LDL, HDL, SBP, Insulin, Ht 9 showed sex-specific linkages 12 / 17 heritability or linkage Conclusions: Sex differences: Conclusions: Sex differences ….. In prevalence abound ….. In heritability for some psychiatric disorders, allergy, CHD phenotypes ……In gene expression for some traits (rg andlt; 1) ……In associations between polymorphisms and outcomes 'Failing to model for sex-specific architecture may substantially hamper detection of susceptibility loci in genome-wide screens, and using modified approaches may increase our power to identify genes underlying complex traits' Weiss et al 2006 Collaborators & Support: Collaborators andamp; Support Depression andamp; Alcohol Margaret Gatz Ken Kendler Carol Prescott Chronic Fatigue Patrick Sullivan Cognitive aging andamp; Alzheimers Chandra Reynolds Deborah Finkel Jack McArdle Sanna Read Margaret Gatz Parkinsons disease Margaret Gatz Karin Wirdefeldt NIH AG 04563, 10175, 08724 NS 041483 ES 10758 Swedish Scientific Council Alzheimer disease and Parkinsonism: 0 Alzheimer disease and Parkinsonism
http://hgm2006.hugo-international.org/Presentations/S7/HGM2006_S7_01_Pedersen.ppt. Preview. ... http://labclinpharm.ru/library/2008_01.ppt. Preview ...