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

Terrie VasilopoulosUniversity of Chicago

Demography Workshop01/10/13

Cognitive performance across the lifespan

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

Heritability of cognition across the lifespan

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

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 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

P = A + C + EVar(P) = a2+c2+e2

A C E EA C

P Twin 1

P Twin 2

1.0 MZ/0.5 DZ 1.0 MZ/1.0 DZ

a c e a c e

A

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

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

• Bioecological model predicts 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:

Child and Adolescent Cognition

• 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 Adolescence

GxE Interactions for Cognition: Child and Adolescence

Rowe et al. (1999) Child Development

• 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 Cognition: Child and Adolescence

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

Kremen et al. (2005) Behavior Genetics

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 Cognition: Childhood 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

GxE Interactions for Cognition: Adult SES Adult Cognition

Developmental Differences 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

• 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

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GeneralIntelligence

Memory ProcessingSpeed

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Stampfer (2006); Birns & Kalra (2008); Singh-Manoux & Marmot (2005); Knecht et al. (2009); van den Berg et al. (2009)

• Hypertension linked to poorer cognitive function

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

• 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

Methods

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• 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• 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

• 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 Medicated Hypertensives

Unmedicated Hypertensives

Non-Hypertensives Medicated Hypertensives

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

Results

BP & demographics across groups

Non-hypertensive n

= 548

Medicated Hypertensive

n = 422

Unmedicated Hypertensive

n = 265

Systolic BP, Mean, (SD) range 125 (8) 98-139

136 (14) 100-178

149 (11) 123-211

Diastolic BP, Mean, (SD) range

79 (6) 58-90

84 (9) 58-118

93 (7) 68-128

Age*, Mean (SD) 55.2 (2.5) 55.8 (2.5) 55.4 (2.5)

BMI*, Mean (SD) 28.1 (2.5) 31.2 (2.5) 29.3 (2.5)

Diabetes diagnosis*, N (% in group) 24 (4.4%) 72 (17.0%) 8 (3.0%)

Cardiovascular Disease diagnosis*, N (% in group)

53 (9.7%) 141 (33.3%) 20 (7.5%)

Education, Mean (SD) 13.8 (2.2) 13.9 (2.1) 13.8 (2.0)

Parental Education, Mean (SD) 11.1 (2.7) 10.9 (2.5) 11.1 (2.3)

AFQT (age 20), Mean percentile (SD) 61.9 (22.5) 60.6 (22.6) 61.1 (22.3)*significant differences across BP groups, subsequent analyses adjusted for these variables

Mean differences across BP groups

• No mean level differences in cognition due to blood pressure group

Non-hypertensives

Medicated Hypertensives

Unmedicated Hypertensives

Visual Spatial Ability 0.04 (0.99) -0.04 (0.99) 0.02 (1.02)

Episodic Memory 0.02 (1.02) 0.00 (0.99) -0.04 (0.98)

Abstract Reasoning 0.00 (0.99) 0.01 (1.05) -0.01 (0.93)

Processing Speed 0.05 (0.99) -0.04 (1.04) -0.04 (0.99)

Executive Function 0.00 (1.05) -0.01 (0.95) 0.02 (0.97)

Working Memory 0.03 (1.00) -0.03 (1.00) -0.02 (0.98)

Short Term Memory 0.03 (0.99) 0.01 (0.99) -0.08 (1.01)

Verbal Ability 0.02 (1.02) -0.01 (1.02) -0.03 (0.93)

Verbal Fluency 0.07 (1.03) -0.07 (0.98) -0.03 (0.96)

General Cognitive Ability 0.03 (0.98) -0.01 (1.02) -0.03 (0.99)

*all cognitive measures were standardized prior to analysis

Univariate heritability estimates(no moderation)

A C E

Visual Spatial Ability 0.69 0.01 0.30

Episodic Memory 0.49 0.03 0.48

Abstract Reasoning 0.44 0.12 0.44

Processing Speed 0.55 0.00 0.45

Executive Function 0.41 0.00 0.59

Short Term Memory 0.58 0.00 0.42

Working Memory 0.30 0.07 0.63

Verbal Ability 0.44 0.17 0.40

Verbal Fluency 0.52 0.00 0.48

General Cognitive Ability 0.64 0.10 0.26

Non-Hypertensives = Medicated HypertensivesHeritability

Non Medχ2

df=2 p

Verbal Ability 0.65 0.59 1.18 0.56

Visual-Spatial Ability 0.73 0.76 0.23 0.89

Episodic Memory 0.62 0.59 0.50 0.78

Abstract Reasoning 0.62 0.58 2.10 0.35

Processing Speed 0.52 0.66 2.99 0.22

Working Memory 0.41 0.36 0.21 0.90

Executive Function 0.44 0.44 2.85 0.15

Short-Term Memory 0.57 0.60 0.18 0.92

Verbal Fluency 0.51 0.56 1.43 0.49

General Cognitive Ability 0.77 0.74 1.66 0.44

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

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

Multiple Group Analysis

Non & Medicated Hypertensives = Unmedicated Hypertensives

Domainχ2

df = 2 p

Visual Spatial Ability 8.62 0.01

Episodic Memory 11.23 0.004

Abstract Reasoning 5.40 0.07

Processing Speed 2.65 0.27

Short-Term Memory 0.44 0.80

Working Memory 0.37 0.83

Verbal Ability 1.96 0.37

Executive Function 1.65 0.43

Verbal Fluency 1.89 0.33

General Cognitive Ability 0.86 0.65

Multiple Group Analysis

Heritability of cognition is lower in Unmedicated Hypertensives vs. Non & Medicated Hypertensives

Visual Spatial Ability

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h2 = 0.75 vs. h2 = 0.55 h2 = 0.61 vs. h2 = 0.25

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Summary and Conclusions

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?

• 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 memory processes

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GeneralIntelligence

Memory ProcessingSpeed

CognitiveFlexibility

Language

Median Effect Size

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

• 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• 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• 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)

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

Thank you!