1. Sex differences in disease predisposition Nancy L. Pedersen Dept. of Medical Epidemiology and Biostatistics Karolinska Institutet and Dept. of Psychology University of Southern California

2. June 3, 20062 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

3. June 3, 20063 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

4. June 3, 20064 Differences in Prevalences – Neuropsychiatric Outcomes  Alcohol dependence & abuse  Autism  Major depression  Chronic fatigue, Chronic widespread pain  Spatial abilities  Alzheimer’s disease  Survival?  Parkinson’s disease

5. June 3, 20065 Differences in prevalences…  Are like means….  Don’t necessarily imply differences in genetic variance (heritability)  Heritability focuses on within group variance

6. June 3, 20066 Paths to finding different heritabilities  Like sexed twin pairs  Compare h 2 in males and females separately α : MZ = 1, DZ =.5

7. June 3, 20067 Sex limitation  Include opposite sex pairs γ OSZ correlation

8. June 3, 20068 0 Patterns of Twin Pair Similarity and Genetic Correlations: Quantitative Sex Differences ♀ h 2 > ♂ h 2

9. June 3, 20069 0 Patterns of Twin Pair Similarity and Genetic Correlations: Sex modified gene expression

10. June 3, 200610 Twin Pair Similarity and Estimated Male-Female Genetic Correlations for Alcoholism Prescott et al 1999, Alcohol Clin Exp Res No quantitative differences i.e., h 2 equal But only partially overlapping, qualtitative differences

11. June 3, 200611 Major Depression Prevalence  Sweden: (N=42,161 indiv)  females 25% males, 13%

12. June 3, 200612 Major Depression Kendler et al. (1999) Virginia

13. June 3, 200613 Major Depression Genetic Correlation ?? Low power Kendler et al. (1999) Virginia Bierut et al. (1999) Australia

14. June 3, 200614 Major Depression Kendler et al. (2005) Am J Psychiatry Genetic Correlation.55 Kendler et al. (2001) Psychol Med Virginia

15. June 3, 200615 Major Depression Gen Corr.63 Kendler et al. (2005) Am J Psychiatry Gen Corr.55 Kendler et al. (2001) Psychol Med VirginiaSweden

16. June 3, 200616 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

17. June 3, 200617 Comorbidity: common liabilities or sex- specific expression? Female Dep Female Alc Liability Female Male Dep Male Alc Liability Male Sex-specific expression Dep 2 Dep Liab Rel 2 Alc 2 Alc Liab Rel 2 Dep 1 Dep Liab Rel 1 Alc 1 Alc Liab Rel 1 Common liabilities r g ♂ =.52 r g ♀ =.39 Prescott et al. (2000) Arch Gen Psychiat

18. June 3, 200618 Chronic Fatigue

19. June 3, 200619 Chronic Fatigue - prevalences

20. June 3, 200620 Chronic Fatigue - heritabilities Increasing degree of severity Sullivan et al. (2005) Psychol Med

21. June 3, 200621 Cognitive abilities

22. June 3, 200622 Two of eleven cognitive measures: sex differences in rates of decline Finkel et al (2006) ANC

23. June 3, 200623 NO!

24. June 3, 200624 Alzheimer disease Gatz et al. (2006) Arch Gen Psychiatry

25. June 3, 200625 Alzheimer disease Parkinsonism  No differences in prevalence  After controlling for age!!!  Indication of shared env in women h 2 =.45, c 2 =.36  Men: h 2 =.58, c 2 =.07  Genetic correlation = 1  No sign sex diff in heritability h 2 =.79  No differences in prevalence  Regardless of age (0.5%)  Significant shared env in men and women Women: c 2 =.18 Men: c 2 =.13  Genetic correlation = 1  Sign sex diff in heritability Women: h 2 =.22 Men: h 2 =.13 Gatz et al. (2006) Arch Gen PsychiatryWirdefeldt et al. (2004) Neurology

26. June 3, 200626 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

27. June 3, 200627 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”

28. June 3, 200628 Consequences for Linkage and Association?

29. June 3, 200629 Association analyses: Depressive symptoms in elderly  h 2 greater in women, association stronger in men  Accounts for more of genetic variance in men? 0.1, 1.1 0.3 0.7 0.7, 1.9 1.2 0.7 Women 0.5, 1.3 1.3 0.8 1.3, 4.4 2.4* 1.3 Men 95% CIOR95% CIOR 5-HT transporter C/C, C/A 5-HTR2A prom A/A, A/C Jansson et al. (2003) Am J Med Gen

30. June 3, 200630 Other sex dependent genetic associations  β 2adrenoceptor and asthma: OR ♂ > 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

31. June 3, 200631

32. June 3, 200632 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

33. June 3, 200633 Conclusions: Sex differences  ….. In prevalence abound  ….. In heritability for some psychiatric disorders, allergy, CHD phenotypes  ……In gene expression for some traits (r g < 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

34. June 3, 200634 Collaborators & Support  Depression & Alcohol  Margaret Gatz  Ken Kendler  Carol Prescott  Chronic Fatigue  Patrick Sullivan  Cognitive aging & 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 

35. June 3, 200635 0 Alzheimer disease and Parkinsonism