sex differences in disease predisposition nancy l. pedersen dept. of medical epidemiology and...
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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
June 3, 2006 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
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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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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
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 - heritabilities
Increasing degree of severity
Sullivan et al. (2005) Psychol Med
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Two of eleven cognitive measures: sex differences in rates of decline
Finkel et al (2006) ANC
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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
June 3, 2006 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”
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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
June 3, 2006 30
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
June 3, 2006 32
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