Sex differences in disease predisposition

Nancy L. Pedersen

Dept. of Medical Epidemiology and Biostatistics

Karolinska Institutet

and

Dept. of Psychology

University of Southern California

June 3, 2006 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

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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

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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

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Differences in prevalences…

Are like means….

Don’t necessarily imply differences in genetic variance (heritability) Heritability focuses on within group variance

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Paths to finding different heritabilities

Like sexed twin pairs

Compare h2 in males and females separately α : MZ = 1, DZ = .5

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Sex limitation

Include opposite sex pairs

γ OSZ correlation

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0

0.1

0.2

0.3

0.4

0.5

0.6

MZF DZF MZM DZM DZOS

tetr

acho

ric c

orre

latio

n

rg=1.0

rg=0.5

rg=0

0

Patterns of Twin Pair Similarity and Genetic Correlations: Quantitative Sex Differences

♀ h2 > ♂ h2

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0

0.1

0.2

0.3

0.4

0.5

0.6

MZF DZF MZM DZM DZOS

tetr

acho

ric c

orre

latio

n

rg=1.0

rg=0.5

rg=0

0

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

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Twin Pair Similarity and Estimated Male-Female Genetic Correlations for Alcoholism

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

MZF DZF MZM DZM DZOS Rg

tetr

acho

ric c

orre

latio

n

Dependence

Abuse or Dep

Mult Thresh

# Depend Sx

Prescott et al 1999, Alcohol Clin Exp Res

No quantitative differences i.e., h2 equal

But only partially overlapping, qualtitative differences

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Major Depression

Prevalence

Sweden: (N=42,161 indiv)

females 25% males, 13%

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Major Depression

0%

20%

40%

60%

80%

100%

Men Women

Shared env

Non-shared env

Genetic

Kendler et al. (1999)

Virginia

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Major Depression

0%

20%

40%

60%

80%

100%

Men Women Men Women

Shared env

Non-shared env

Genetic

Genetic Correlation

??Low power

Kendler et al. (1999)

Virginia

Bierut et al. (1999)

Australia

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Major Depression

0%

20%

40%

60%

80%

100%

Men Women

Shared env

Non-shared env

Genetic

Kendler et al. (2005) Am J Psychiatry

Genetic Correlation

.55

Kendler et al. (2001) Psychol Med

Virginia

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Major Depression

0%

20%

40%

60%

80%

100%

Men Women Men Women

Shared env

Non-shared env

GeneticGen Corr.63

Kendler et al. (2005) Am J Psychiatry

Gen Corr.55

Kendler et al. (2001) Psychol Med

Virginia Sweden

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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

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Comorbidity: common liabilities or sex-specific expression?

FemaleDep

FemaleAlc

LiabilityFemale

MaleDep

MaleAlc

LiabilityMale

Sex-specific expression

Dep 2

Dep LiabRel 2

Alc 2

Alc LiabRel 2

Dep 1Dep Liab

Rel 1

Alc 1Alc Liab

Rel 1

Common liabilities

rg ♂ = .52

rg ♀ = .39

Prescott et al. (2000) Arch Gen Psychiat

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Chronic Fatigue

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Chronic Fatigue - prevalences

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Chronic Fatigue - heritabilities

Increasing degree of severity

Sullivan et al. (2005) Psychol Med

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Cognitive abilities

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Two of eleven cognitive measures: sex differences in rates of decline

Finkel et al (2006) ANC

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NO!

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Alzheimer disease

Gatz et al. (2006) Arch Gen Psychiatry

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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 heritabilityWomen: h2 = .22

Men: h2 = .13Gatz et al. (2006) Arch Gen Psychiatry Wirdefeldt et al. (2004) Neurology

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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

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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”

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Consequences for Linkage and Association?

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Association analyses: Depressive symptoms in elderly

h2 greater in women, association stronger in men Accounts for more of genetic variance in men?

0.1, 1.10.3

0.7

0.7, 1.91.2

0.7

Women

0.5, 1.31.3

0.8

1.3, 4.42.4*

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

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Other sex dependent genetic associations

β2adrenoceptor and asthma: OR♂ > OR♀Santillan et al (2003) J Allergy Clin Immunol

DISC1 and SchizophreniaHennah et al (2003) Hum Mol Genet

MMP3 promotor in men and celiac diseaseMora et al (2005) Hum Immunol

MTHFR assoc with lung cancer in womenShi et al (2005) Cancer Epidemiol Biomarkers Prev

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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

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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

June 3, 2006 34

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

June 3, 2006 35

0

0.1

0.2

0.3

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0.5

0.6

0.7

0.8

0.9

1

MZF DZF MZM DZM DZOS

tetr

acho

ric c

orre

latio

n

AD

Column 2

PD

0

Alzheimer disease and Parkinsonism