Presentation Transcript

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!