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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)


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


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


Univariate heritability estimates no moderation
Univariate heritability estimates(no moderation)


Non hypertensives medicated hypertensives

Multiple Group Analysis

Non-Hypertensives = Medicated Hypertensives


Non hypertensives unmedicated hypertensives

Multiple Group Analysis

Non-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 Analysis

Medicated 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


Non medicated hypertensives unmedicated hypertensives

Multiple Group Analysis

Non & Medicated Hypertensives = Unmedicated Hypertensives


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


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 performance differences?

  • 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 performance differences?

  • 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 performance differences?

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)


Thank you
Thank you! performance differences?


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