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Cognition and Hypertension in Midlife: Evidence for Gene-Environment Interplay. Terrie Vasilopoulos University of Chicago Demography Workshop 01/10/13. Cognitive performance across the lifespan. Hedden & Gabrieli (2004) Nature Reviews Neuroscience , 5 , 87-96.

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cognition and hypertension in midlife evidence for gene environment interplay

Cognition and Hypertension in Midlife: Evidence for Gene-Environment Interplay

Terrie Vasilopoulos

University of Chicago

Demography Workshop

01/10/13

cognitive performance across the lifespan
Cognitiveperformance across the lifespan

Hedden & Gabrieli (2004) Nature Reviews Neuroscience, 5, 87-96

heritability of cognition across the lifespan
Heritability of cognition across the lifespan

Haworth et al. (2010); Grant et al. (2010); McClearn et al. (1998)

behavioral genetics
Behavioral Genetics
  • Understand individual differences in traits
  • Decompose phenotypic variation into 3 components:
  • A  additive genetic
    • Genetic influences shared between relatives
  • C  shared environment
    • Non-genetic factors that make relatives similar
  • E  non-shared environment
    • Non-genetic factors that make relatives dissimilar
behavioral genetics1
Behavioral Genetics
  • Twins studies  one of the most common behavioral genetic designs
  • Monozygotic twins (MZ)  Identical
  • Dizygotic twins (DZ)  Fraternal
  • A  additive genetic
    • MZ = 100%, DZ = ~50%
  • C  shared environment
    • MZ & DZ = 100%
  • E  non-shared environment
    • MZ & DZ = 0%
  • Other sibling/family structures can be used following similar assumptions
twin method
Twin Method

1.0 MZ/0.5 DZ

1.0 MZ/1.0 DZ

A

A

C

E

A

C

E

a

c

e

a

c

e

P Twin 1

P Twin 2

P = A + C + E

Var(P) = a2+c2+e2

** Heritability (h2) = A/P **

extensions of twin method
Extensions of Twin Method
  • Multivariate Relationships
  • Longitudinal Change
  • Sex Differences
  • Gene-Environment Interactions/Interplay (GxE)
    • How do genetic influences (heritability) differ across various environments?
theories of gene environment interplay
Theories of Gene-Environment Interplay
  • Bioecological modelpredicts that adverse environments suppress “genetic potential” (Brofenbrenner and Ceci, 1994)
    • Other early theories of gene-environment interplay suggest genetic differences enhanced in “good enough” environments (Scarr, 1992)
  • Diathesis-Stress model predicts the opposite, with genetic influences greater in high risk environments (Gottesman, 1991)
slide9
Lifestyle Health

Genes

Cognition

gxe interactions for cognition

GxE Interactions for Cognition:

Child and Adolescent Cognition

gxe interactions for cognition child and adolescence
GxE Interactions for Cognition: Child and Adolescence
  • Rowe, Jacobson and van den Oord (1999)
    • Moderating effects of family “environment” on heritability of cognitive ability
      • Vocabulary IQ
      • Parental education level
    • Used data from twins, full-, half-, and unrelated siblings, and cousins from the AddHealth Study
    • Found that genetic variance ↑, and shared environmental variance ↓, among adolescents with more highly educated parents
gxe interactions for cognition child and adolescence1
GxE Interactions for Cognition: Child and Adolescence

Rowe et al. (1999) Child Development

gxe interactions for cognition child and adolescence2
GxE Interactions for Cognition: Child and Adolescence
  • Turkheimer et al. (2003)
    • Full-Scale IQ, Verbal IQ and Performance IQ
    • 7 year olds
    • Parental education, income and occupation
  • Harden et al. (2006)
    • National Merit Scholar Qualification Test
    • 17 year olds
    • Parental education and Income
  • Friend et al. (2008)
    • Reading Disability
    • 8-20 years
    • Parental Education
gxe interactions for cognition1

GxE Interactions for Cognition:

Childhood SES Adult Cognition

gxe interactions for cognition childhood ses adult cognition
GxE Interactions for Cognition: Childhood SES Adult Cognition
  • Kremen et al. (2005)
    • Middle-Aged Male twins (51-60 yrs) from Vietnam-Era Twin Study of Aging (VETSA)
    • Verbal Ability
    • Parental Education
    • ↓ shared environmental variance with ↑ parental education
    • Stable genetic variance
    • no direct genetic moderation
gxe interactions for cognition childhood ses adult cognition1
GxE Interactions for Cognition: Childhood SES Adult Cognition

Kremen et al. (2005) Behavior Genetics

gxe interactions for cognition childhood ses adult cognition2
GxE Interactions for Cognition: Childhood SES Adult Cognition
  • van der Sluis et al. (2008)
    • FSIQ
    • Shared environmental variance of IQ moderated by parental education
    • Stable genetic variance
    • no genetic moderation
    • Men  mean age 49 yrs (36-69 yrs)
  • Grant et al. (2010) - VETSA
    • general cognitive ability
    • ↑ total variance due to parental education
    • no genetic moderation
gxe interactions for cognition2

GxE Interactions for Cognition:

Adult SES Adult Cognition

gxe interactions for cognition adult ses adult cognition
GxE Interactions for Cognition: Adult SES Adult Cognition
  • van der Sluis et al. (2008)
    • FSIQ
    • ↑ non-shared environmental variance with higher mean real estate prices of participants’ residential area
    • Stable genetic variance
    • no genetic moderation
  • Vasilopoulos et al. (unpublished)
    • General Cognitive Ability - VETSA
    • Non-shared environmental variance moderated by individuals lifetime education
    • Stable genetic variance
    • no genetic moderation
developmental differences in gxe
DevelopmentalDifferences in GxE?
  • Prior research suggests that the moderating effects of childhood family environments (e.g., family socioeconomic status) may not have lasting effects on genetic variance in adult cognition
  • Lack of evidence for genetic moderation by adult SES
  • Are there other adult environmental or behavioral factors that enhance or suppress genetic variance in cognition?
physical health and cognition
Physical Health and Cognition
  • Many physical factors associated with cognitive function
    • Pulmonary function
    • Grip strength
    • Physical fitness
    • Bioage
  • Physiological factors  gene expression in brain
    • Caloric restriction
    • Exercise
    • Diet

Chyou et al. (1996); Alfaro-Acha et al. (2006); Anstey and Smith (1999); Macdonald et al. (2004); Salthouse et al. (1998); Johnson et al. (2009); Emery et al. (1998); Cotman & Berchtold (2002); Kitajka et al. (2002); Weindruch et al. (2002)

hypertension and cognition
Hypertension and Cognition
  • Hypertension linked to poorer cognitive function
  • Stampfer (2006); Birns & Kalra (2008); Singh-Manoux & Marmot (2005); Knecht et al. (2009); van den Berg et al. (2009)
antihypertensive medication
Antihypertensive medication
  • Many studies adjust for antihypertensive medication use
  • Evidence for direct influence on cognition
    • 36% reduced odds of cognitive impairment
    • 8% reduction in dementia risk
  • Murray et al. (2002); Haag et al. (2009)
study objectives
Study Objectives
  • Examine the extent that hypertension modifies the influence of genetic and environmental factors on cognition at midlife
  • Assess how antihypertensive medication use alters the effect of hypertension on cognition
sample and procedures
Sample and Procedures
  • Vietnam-Era Twin Study of Aging (VETSA)
    • longitudinal study of cognition and aging, beginning at midlife
    • nationally representative, male-male twin pairs from VET Registry
    • 1237 individuals (Wave 1)
      • 697 MZ, 540 DZ
    • Twins traveled to either University of California, San Diego or Boston University for day-long testing session
      • Assessments of cognitive performance and physical health
    • Age: 55.4 years old (51-60 years)
    • Wave 2 ongoing through 2013
measures blood pressure
Measures: Blood Pressure
  • Mean of 4 measurements taken during day-long testing session
  • Three blood pressure groups:
  • Non-hypertensive: n = 548 (44.4%)
    • systolic/diastolic < 140/90 mm hg
  • Medicated Hypertensive: n = 422 (34.2%)
    • diagnosed hypertensive with self-reported use of antihypertensive medication
  • Unmedicated Hypertensive: n = 265 (21.4%)
    • systolic ≥ 140 mm hg or diastolic ≥ 90 mm hg, untreated by antihypertensive medication
measures cognition
Measures: Cognition
  • Standardized composites of separate cognitive tests were used to construct domains
    • Visual Spatial Ability (Hidden Figures, Card Rotation)
    • Episodic Memory (Logical Memory, Visual Reproduction)
    • Abstract Reasoning (Matrix Reasoning)
    • Processing Speed (Trails 2 & 3, Stroop Word)
    • Executive Function (Trails 4, Verbal Fluency)
    • Working Memory (Digit and Spatial Span Backward, Letter-Number Sequencing)
    • Short Term Memory (Digit and Spatial Span Forward)
    • Verbal Ability (Vocabulary)
    • Verbal Fluency(Category Fluency)
    • General Cognitive Ability Armed Forces Qualification Test (AFQT)
analysis multiple group approach to test for gxe
Analysis: Multiple Group approach to test for GxE
  • Split the sample into three groups based on blood pressure and antihypertensive medication use
    • Non-hypertensive (Non)
    • Medicated Hypertensive (Med)
    • Unmedicated Hypertensive (Unmed)
  • Assigned each twin to a blood pressure group (Non, Med, or Unmed)
    • Created data groups that included twins concordant and discordant for BP group status
    • Use these data groups to estimate genetic and environmental variance for each BP group
slide30
Non-Hypertensives

Non-Hypertensives

Medicated Hypertensives

Medicated Hypertensives

Unmedicated Hypertensives

model fitting
Model Fitting
  • Baseline model ACE allowed to differ among BP groups
  • Submodels
    • Non = Med
    • Non = UnMed
    • Med = UnMed
  • Compare model fits using difference -2 Log Likelihood
    • Follows a chi-square (X2) distribution
    • Significant X2 indicates ACE cannot be equated
      • ACE across BP are significantly different
bp demographics across groups
BP & demographics across groups

*significant differences across BP groups, subsequent analyses adjusted for these variables

mean differences across bp groups
Mean differences across BP groups
  • No mean level differences in cognition due to blood pressure group

*all cognitive measures were standardized prior to analysis

non hypertensives unmedicated hypertensives
Multiple Group AnalysisNon-Hypertensives = Unmedicated Hypertensives
  • Visual Spatial Ability
    • χ2 = 5.90, df = 2, p = 0.05
  • Episodic Memory
    • χ2 = 9.32, df = 2, p = 0.01
  • Support for both GxE and ExE
medicated hypertensives unmedicated hypertensives
Multiple Group AnalysisMedicated Hypertensives = Unmedicated Hypertensives
  • Visual Spatial Ability
    • χ2 = 7.45, df = 2, p = 0.02
  • Episodic Memory
    • χ2 = 9.35, df = 2, p = 0.01
  • Support for both GxE and ExE
heritability of cognition is lower in unmedicated hypertensives vs non medicated hypertensives
Heritability of cognition is lower in Unmedicated Hypertensives vs. Non & Medicated Hypertensives

E

A

A

A

E

E

A

E

h2 = 0.75 vs. h2 = 0.55

h2 = 0.61 vs. h2 = 0.25

summary of results
Summary of Results
  • No mean differences due to blood pressure group
  • Heritability estimates were lower in unmedicated hypertensives versus non-hypertensives/medicated hypertensives
    • Visual Spatial Ability
    • Episodic Memory
  • Heritability estimates could be equated between non-hypertensives and medicated hypertensives
why are results domain specific
Why are results domain-specific?
  • Visual spatial ability and episodic memory are some of the first processes affected by AD and aging
  • Hypertension-related cognitive deficits most often reported in memoryprocesses
slide44
Why might we see differences in genetic effects prior to performance differences?
  • Blalock et al. (2003)

**Genetic changes may be a measurable precursor to observed cognitive changes**

medication as a buffer against adverse effects
Medication as a buffer against adverse effects
  • Bioecological model and “good enough” environments hypothesis
  • Untreated hypertension may be viewed as a poor “internal environment”
  • Medication use returns internal environment to a more favorable state
conclusions
Conclusions
  • Heritability of cognition is dynamic
  • Early life experiences childhood and adolescence cognition
    • Not present in our sample of middle-aged men
  • Physical health  adult cognition
    • Untreated hypertension moderates genetic and environmental influences of cognition in midlife
  • Developmental differences in what types of environments influence genetic factors underlying cognition
  • Future GxE studies of cognition need to take a developmentally driven approach
acknowledgements
Acknowledgements

Vasilopoulos et al. (2012). Untreated Hypertension Decreases Heritability of Cognition in Late Middle Age. Behavior Genetics. DOI: 10.1007/s10519-011-9479-9

  • University of Chicago
    • Kristen C. Jacobson
  • University of California, San Diego
    • William S. Kremen
    • Carol E. Franz
    • Matthew S. Panizzon
    • Kathleen Kim
  • Washington University School of Medicine
    • Phyllis K. Stein
  • Saint Louis University
    • Hong Xian
  • Boston University
    • Michael J. Lyons
    • Michael D. Grant
    • Rosemary Toomey
  • Virginia Commonwealth University
    • Lindon J. Eaves
  • Funding
    • NIH/NIA (F32 AG039954. R01 AG018386, R01 AG018384, R01 AG022381, and R01 AG022982)
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