1 / 35

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. Differences in prevalences and variance components Neuropsychiatric outcomes

ghita
Download Presentation

Sex differences in disease predisposition

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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. 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. 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. 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. Differences in prevalences… • Are like means…. • Don’t necessarily imply differences in genetic variance (heritability) • Heritability focuses on within group variance

  6. Paths to finding different heritabilities • Like sexed twin pairs • Compare h2 in males and females separately α : MZ = 1, DZ = .5

  7. Sex limitation • Include opposite sex pairs γOSZ correlation

  8. Patterns of Twin Pair Similarity and Genetic Correlations: Quantitative Sex Differences ♀ h2 > ♂ h2 0

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

  10. Twin Pair Similarity and Estimated Male-Female Genetic Correlations for Alcoholism No quantitative differences i.e., h2 equal But only partially overlapping, qualtitative differences Prescott et al 1999, Alcohol Clin Exp Res

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

  12. Major Depression Virginia Kendler et al. (1999)

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

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

  15. Major Depression Virginia Sweden Gen Corr .55 Gen Corr .63 Kendler et al. (2001) Psychol Med Kendler et al. (2005) Am J Psychiatry

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

  18. Chronic Fatigue

  19. Chronic Fatigue - prevalences

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

  21. Cognitive abilities

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

  23. NO!

  24. Alzheimer disease Gatz et al. (2006) Arch Gen Psychiatry

  25. 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 Alzheimer disease Parkinsonism Gatz et al. (2006) Arch Gen Psychiatry Wirdefeldt et al. (2004) Neurology

  26. 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?

  27. 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. Consequences for Linkage and Association?

  29. 5-HTR2Aprom A/A , A/C 5-HT transporter C/C, C/A OR 95% CI OR 95% CI Men 2.4* 1.3 1.3, 4.4 1.3 0.8 0.5, 1.3 Women 1.2 0.7 0.7, 1.9 0.3 0.7 0.1, 1.1 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

  30. Other sex dependent genetic associations • β2adrenoceptor 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. Consequences for linkage studiesWeiss 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

  32. Conclusions: Sex differences • ….. In prevalence abound • ….. In heritability for some psychiatric disorders, allergy, CHD phenotypes • ……In gene expression for some traits (rg < 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

  33. 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 Collaborators & Support

  34. Alzheimer disease and Parkinsonism 0

More Related