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

1. Cognition and Hypertension in Midlife: Evidence for Gene-Environment Interplay Terrie Vasilopoulos University of Chicago Demography Workshop 01/10/13

2. Cognitiveperformance across the lifespan Hedden & Gabrieli (2004) Nature Reviews Neuroscience, 5, 87-96

3. Heritability of cognition across the lifespan Haworth et al. (2010); Grant et al. (2010); McClearn et al. (1998)

4. 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

5. 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

6. 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 **

7. Extensions of Twin Method • Multivariate Relationships • Longitudinal Change • Sex Differences • Gene-Environment Interactions/Interplay (GxE) • How do genetic influences (heritability) differ across various environments?

8. 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)

9. Lifestyle Health Genes Cognition

10. GxE Interactions for Cognition: Child and Adolescent Cognition

11. 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

12. GxE Interactions for Cognition: Child and Adolescence Rowe et al. (1999) Child Development

13. 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

14. GxE Interactions for Cognition: Childhood SES Adult Cognition

15. 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

16. GxE Interactions for Cognition: Childhood SES Adult Cognition Kremen et al. (2005) Behavior Genetics

17. 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

18. GxE Interactions for Cognition: Adult SES Adult Cognition

19. 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

20. 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?

21. 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)

22. 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)

23. 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)

24. 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

25. Methods

26. 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

27. 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

28. 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)

29. 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

30. Non-Hypertensives Non-Hypertensives Medicated Hypertensives Medicated Hypertensives Unmedicated Hypertensives

31. 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

32. Results

33. BP & demographics across groups *significant differences across BP groups, subsequent analyses adjusted for these variables

34. Mean differences across BP groups • No mean level differences in cognition due to blood pressure group *all cognitive measures were standardized prior to analysis

35. Univariate heritability estimates(no moderation)

36. Multiple Group Analysis Non-Hypertensives = Medicated Hypertensives

37. 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

38. 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

39. Multiple Group Analysis Non & Medicated Hypertensives = Unmedicated Hypertensives

40. 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

41. Summary and Conclusions

42. 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

43. 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

44. 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**

45. 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

46. 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

47. 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)

48. Thank you!