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A Meta-analysis of Heritability of Cognitive Aging: Minding the “Missing Heritability” Gap

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Abstract

The etiologies underlying variation in adult cognitive performance and cognitive aging have enjoyed much attention in the literature, but much of that attention has focused on broad factors, principally general cognitive ability. The current review provides meta-analyses of age trends in heritability of specific cognitive abilities and considers the profile of genetic and environmental factors contributing to cognitive aging to address the ‘missing heritability’ issue. Our findings, based upon evaluating 27 reports in the literature, indicate that verbal ability demonstrated declining heritability, after about age 60, as did spatial ability and perceptual speed more modestly. Trends for general memory, working memory, and spatial ability generally indicated stability, or small increases in heritability in mid-life. Equivocal results were found for executive function. A second meta-analysis then considered the gap between twin-based versus SNP-based heritability derived from population-based GWAS studies. Specifically, we considered twin correlation ratios to agnostically re-evaluate biometrical models across age and by cognitive domain. Results modestly suggest that nonadditive genetic variance may become increasingly important with age, especially for verbal ability. If so, this would support arguments that lower SNP-based heritability estimates result in part from uncaptured non-additive influences (e.g., dominance, gene-gene interactions), and possibly gene-environment (GE) correlations. Moreover, consistent with longitudinal twin studies of aging, as rearing environment becomes a distal factor, increasing genetic variance may result in part from nonadditive genetic influences or possible GE correlations. Sensitivity to life course dynamics is crucial to understanding etiological contributions to adult cognitive performance and cognitive aging.

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Notes

  1. We note that while others refer to GxE as contributing to the missing heritability presumably this refers to GxC where C refers to the common environment, as Gx(nonshared)E leads to dissimilarity amongst relatives.

References

  • Baker, L. A., Treloar, S. A., Reynolds, C. A., Heath, A. C., & Martin, N. G. (1996). Genetics of educational attainment in Australian twins: sex differences and secular changes. Behavior Genetics, 26(2), 89–102.

    Article  CAS  PubMed  Google Scholar 

  • Bergen, S. E., Gardner, C. O., & Kendler, K. S. (2007). Age-related changes in heritability of behavioral phenotypes over adolescence and young adulthood: a meta-analysis. Twin Research and Human Genetics, 10, 423–433.

    Article  PubMed  Google Scholar 

  • Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C., Harrell, L. E., et al. (1997). Apoe-4 and age at onset of Alzheimer’s disease: the Nimh genetics initiative. Neurology, 48(1), 139–147.

    Article  CAS  PubMed  Google Scholar 

  • Bloom, J. S., Ehrenreich, I. M., Loo, W. T., Lite, T. L., & Kruglyak, L. (2013). Finding the sources of missing heritability in a yeast cross. Nature, 494(7436), 234–237.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boker, S., Neale, M., Maes, H., Wilde, M., Spiegel, M., Brick, T., et al. (2011). Openmx: an open source extended structural equation modeling framework. Psychometrika, 76(2), 306–317.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bouchard, T. J. (2013). The Wilson effect: the increase in heritability of Iq with age. Twin Research and Human Genetics, 16(5), 923–930.

    Article  PubMed  Google Scholar 

  • Bouchard, T. J., & McGue, M. (1981). Familial studies of intelligence: A review. Science, 212, 1055–1059.

  • Chipuer, H. M., Rovine, M. J., & Plomin, R. (1990). Lisrel modeling: genetic and environmental influences on IQ revisited. Intelligence, 14(1), 11–29.

  • Christiansen, K., & McGue, M. (2013). Growing old but not growing apart: twin Aimilarity in the latter half of the lifespan. Behavior Genetics, 43, 1–12.

    Article  Google Scholar 

  • Davies, G., Tenesa, A., Payton, A., Yang, J., Harris, S. E., Liewald, D., et al. (2011). Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Molecular Psychiatry, 16(10), 996–1005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davies, G., Harris, S. E., Reynolds, C. A., Payton, A., Knight, H. M., Liewald, D. C., et al. (2014). A genome-wide association study implicates the Apoe locus in Nonpathological cognitive ageing. Molecular Psychiatry, 19(1), 76–87.

    Article  CAS  PubMed  Google Scholar 

  • Deary, I. J., Yang, J., Davies, G., Harris, S. E., Tenesa, A., Liewald, D., et al. (2012). Genetic contributions to stability and change in intelligence from childhood to old age. Nature, 481(7384), 212–215.

    Google Scholar 

  • Eichler, E. E., Flint, J., Gibson, G., Kong, A., Leal, S. M., Moore, J. H., et al. (2010). Missing heritability and strategies for finding the underlying causes of complex disease. Nature Reviews Genetics, 11(6), 446–450.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Erlenmeyer-Kimling, L., & Jarvik, L. F. (1963). Genetics and intelligence: A review. Science, 142, 1477–1479.

  • Falconer, D. S., & Mackay, T. F. C. (1996). Introduction to quantitative genetics. Essex, UK: Longman Group Ltd.

  • Finch, C. E., & Kirkwood, T. B. (2000). Chance, development, and aging. Oxford: Oxford University Press.

    Google Scholar 

  • Finkel, D., & Reynolds, C. A. (2009). Behavioral genetic investigations of cognitive aging. In Y.-K. Kim (Ed.), Handbook of behavior genetics (pp. 101–112). New York: Springer.

    Chapter  Google Scholar 

  • Finkel, D., & Reynolds, C. A. (2010). Cognitive and physical aging pathways: contributions from behavioral genetics. In J. C. Cavanaugh & C. K. Cavanaugh (Eds.), Aging in America: Volume 2: Physical and mental health (pp. 26–56). Denver: Praeger Publishing.

    Google Scholar 

  • Finkel, D., Reynolds, C. A., McArdle, J. J., Gatz, M., & Pedersen, N. L. (2003). Latent growth curve analyses of accelerating decline in cognitive abilities in late adulthood. Developmental Psychology, 39(3), 535–550.

    Article  PubMed  Google Scholar 

  • Finkel, D., Reynolds, C. A., Larsson, M., Gatz, M., & Pedersen, N. L. (2011). Both odor identification and Apoe-Epsilon4 contribute to normative cognitive aging. Psychology and Aging, 26(4), 872–883.

    Article  PubMed Central  PubMed  Google Scholar 

  • Gatz, M., Jang, J. Y., Karlsson, I. K., & Pedersen, N. L. (2014). Dementia: genes, environments, interactions. In D. Finkel & C. A. Reynolds (Eds.), Behavior genetics of cognition across the lifespan (Vol. 1, pp. 201–231). New York: Springer.

    Chapter  Google Scholar 

  • Gusev, A., Bhatia, G., Zaitlen, N., Vilhjalmsson, B. J., Diogo, D., Stahl, E. A., et al. (2013). Quantifying missing heritability at known Gwas Loci. PLoS Genetics, 9(12), e1003993.

    Article  PubMed Central  PubMed  Google Scholar 

  • Hamilton, W. D. (1966). The moulding of senescence by natural selection. Journal of Theoretical Biology, 12, 12–45.

    Article  CAS  PubMed  Google Scholar 

  • Heath, A. C., Berg, K., Eaves, L. J., Solaas, M. H., Corey, L. A., Sundet, J., et al. (1985). Education policy and the heritability of educational attainment. Nature, 314(6013), 734–736.

    Article  CAS  PubMed  Google Scholar 

  • Hemani, G., Knott, S., & Haley, C. (2013). An evolutionary perspective on epistasis and the missing heritability. PLoS Genetics, 9(2), e1003295.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill, W. G., Goddard, M. E., & Visscher, P. M. (2008). Data and theory point to mainly additive genetic variance for complex traits. PLoS Genetics, 4(2), e1000008.

    Article  PubMed Central  PubMed  Google Scholar 

  • Honea, R. A., Cruchaga, C., Perea, R. D., Saykin, A. J., Burns, J. M., Weinberger, D. R., et al. (2013). Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer’s Disease neurodegeneration. PloS One, 8(9), e76001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Horn, J. L., & Cattell, R. B. (1966). Age differences in primary mental ability factors. Journal of Gerontology, 21(2), 210–220.

    Article  CAS  PubMed  Google Scholar 

  • Horn, J. L., & Cattell, R. B. (1967). Age differences in fluid and crystallized intelligence. Acta Psychologica, 26(2), 107–129.

    Article  CAS  PubMed  Google Scholar 

  • Hox, J. (2010). Multilevel analysis: Techniques and applications. (Second ed.). New York: Routledge.

  • Johansson, B., Hofer, S. M., Allaire, J. C., Maldonado-Molina, M. M., Piccinin, A. M., Berg, S., et al. (2004). Change in cognitive abilities in the oldest old: the effects of proximity to death in genetically related individuals over a 6-year period. Psychology and Aging, 19, 145–156.

    Article  PubMed  Google Scholar 

  • Johnson, W., McGue, M., & Deary, I. J. (2014). Normative cognitive aging. In D. Finkel & C. A. Reynolds (Eds.), Behavior genetics of cognition across the lifespan (pp. 169–200). New York: Springer.

    Google Scholar 

  • Kambeitz, J. P., Bhattacharyya, S., Kambeitz-Ilankovic, L. M., Valli, I., Collier, D. A., & McGuire, P. (2012). Effect of Bdnf Val(66)Met polymorphism on declarative memory and its neural substrate: a meta-analysis. Neuroscience and Biobehavioral Reviews, 36(9), 2165–2177.

    Article  CAS  PubMed  Google Scholar 

  • Kaprio, J. (2012). Twins and the mystery of missing heritability: the contribution of gene-environment interactions. Journal of Internal Medicine, 272(5), 440–448.

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood, T. B. L., Cordell, H. J., & Finch, C. E. (2011). Speed-bumps ahead for the genetics of later-life diseases. Trends in Genetics, 27(10), 387–388.

    Article  CAS  PubMed  Google Scholar 

  • Koch, L. (2014). Epigenetics: an epigenetic twist on the missing heritability of complex traits. Nature Reviews Genetics, 15(4), 218.

    CAS  Google Scholar 

  • Koots, K. R., & Gibson, J. P. (1996). Realized sampling variances of estimates of genetic parameters and the difference between genetic and phenotypic correlations. Genetics, 143, 1409–1416.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lambert, J. C., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s Disease. Nature Genetics, 45(12), 1452–1458.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee, T., Henry, J. D., Trollor, J. N., & Sachdev, P. (2010). Genetic influences on cognitive functions in the elderly: A selective review of twin studies. Brain Research Review, 64(1), 1–13. doi:10.1016/j.brainresrev.2010.02.001.

  • Lessov-Schlagger, C. N., Swan, G. E., Reed, T., Wolf, P. A., & Carmelli, D. (2007). Longitudinal genetic analysis of executive function in elderly men. Neurobiology of Aging, 28, 1759–1768.

    Article  Google Scholar 

  • Liu, D. J., & Leal, S. M. (2012). Estimating genetic effects and quantifying missing heritability explained by identified rare-variant associations. American Journal of Human Genetics, 91(4), 585–596.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maher, B. (2008). Personal genomes: the case of the missing heritability. Nature, 456(7218), 18–21.

    Article  CAS  PubMed  Google Scholar 

  • Maki-Tanila, A., & Hill, W. G. (2014). Influence of gene interaction on complex trait variation with multilocus models. Genetics, 198(1), 355–367.

    Article  PubMed Central  PubMed  Google Scholar 

  • Mandelman, S. D., & Grigorenko, E. L. (2012). Bdnf Val66met and cognition: all, none, or some? A meta-analysis of the genetic association. Genes, Brain and Behavior, 11(2), 127–136.

    Article  CAS  Google Scholar 

  • McArdle, J. J., Prescott, C. A., Hamagami, F., & Horn, J. L. (1998). A contemporary method for developmental-genetic analyses of age changes in intellectual abilities. Developmental Neuropsychology, 14, 69–114.

    Article  Google Scholar 

  • McArdle, J. J., Hamagami, F., Meredith, W., & Bradway, K. P. (2000). Modeling the dynamic hypotheses of gf-gc theory using longitudinal life-span data. Learning and Individual Differences, 12(1), 53–79.

    Article  Google Scholar 

  • McArdle, J. J., Ferrer-Caja, E., Hamagami, F., & Woodcock, R. W. (2002). Comparative longitudinal structural analyses of the growth and decline of multiple intellectual abilities over the life span. Developmental Psychology, 38(1), 115–142.

    Article  PubMed  Google Scholar 

  • McCartney, K., Harris, M. J., & Bernieri, F. (1990). Growing up and growing apart: a development meta-analysis of twin studies. Psychological Bulletin, 107(2), 226–237.

    Article  CAS  PubMed  Google Scholar 

  • Muthén, L. K., & Muthén, B. O. (1998–2012). Mplus user’s guide. (Seventh edition ed.). Los Angeles, CA: Muthén & Muthén

  • Pedersen, N. L., Christensen, K., Dahl, A. K., Finkel, D., Franz, C. E., Gatz, M., et al. (2013). Igems: the consortium on interplay of genes and environment across multiple studies. Twin Research and Human Genetics, 16(1), 481–489.

    Article  PubMed Central  PubMed  Google Scholar 

  • Plomin, R. (2013). Commentary: missing heritability, polygenic scores, and gene–environment correlation. Journal of Child Psychology and Psychiatry, 54(10), 1147–1149.

    Article  PubMed Central  PubMed  Google Scholar 

  • Plomin, R., DeFries, J. C., Knopik, V. S., & Neiderhiser, J. M. (2013a). Behavioral genetics (6th ed.). New York: Worth.

    Google Scholar 

  • Plomin, R., Haworth, C. M. A., Meaburn, E. L., Price, T. S., & Davis, O. S. P. (2013b). Common DNA markers can account for more than half of the genetic influence on cognitive abilities. Psychological Science, 24(4), 562–568.

    Article  PubMed Central  PubMed  Google Scholar 

  • Prescott, C. A. (2004). Using the Mplus computer program to estimate models for continuous and categorical data from twins. Behavior Genetics, 34(1), 17–40.

    Article  PubMed  Google Scholar 

  • Raz, N. (2000). Aging of the brain and its impact on cognitive performance: integration of structural and functional findings. In F. I. M. Craik & T. A. Salthouse (Eds.), The handbook of aging and cognition (2nd ed., pp. 1–90). Hillsdale: Erlbaum.

    Google Scholar 

  • Reynolds, C. A., & Finkel, D. (2015). Cognitive and physical aging: genetic influences and gene–environment interplay. In: K. W. Schaie & S. L. Williis (Eds.), Handbook of the psychology of aging (8th ed.): Academic Press. (in press)

  • Reynolds, C. A., & Phillips, D. (2015). Genomics of brain aging–twin aging. Encyclopedia of Biomedical Sciences. Elsevier. (in press)

  • Reynolds, C. A., Finkel, D., McArdle, J. J., Gatz, M., Berg, S., & Pedersen, N. L. (2005). Quantitative genetic analysis of latent growth curve models of cognitive abilities in adulthood. Developmental Psychology, 41, 3–16.

    Article  PubMed  Google Scholar 

  • Reynolds, C. A., Prince, J. A., Feuk, L., Brookes, A. J., Gatz, M., & Pedersen, N. L. (2006). Longitudinal memory performance during normal aging: twin association models of Apoe and other Alzheimer candidate genes. Behavior Genetics, 36(2), 185–194.

    Article  PubMed  Google Scholar 

  • Reynolds, C. A., Gatz, M., Berg, S., & Pedersen, N. L. (2007). Genotype–environment interactions: cognitive aging and social factors. Twin Research and Human Genetics, 10(2), 241–254.

    Article  PubMed  Google Scholar 

  • Reynolds, C. A., Zavala, C., Gatz, M., Vie, L., Johansson, B., Malmberg, B., et al. (2013). Sortilin receptor 1 predicts longitudinal cognitive change. Neurobiology of Aging, 34(6), 1710. e1711–1718.

    Article  PubMed  Google Scholar 

  • Reynolds, C. A., Finkel, D., & Zavala, C. (2014). Gene by environment interplay in cognitive aging. In D. Finkel & C. A. Reynolds (Eds.), Behavior genetics of cognition across the lifespan (Vol. 1, pp. 169–199). New York: Springer.

    Chapter  Google Scholar 

  • Ridge, P. G., Mukherjee, S., Crane, P. K., Kauwe, J. S., & Alzheimer’s Disease Genetics, C. (2013). Alzheimer’s disease: analyzing the missing heritability. PLoS One, 8(11), e79771.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rowe, S. J., Rowlatt, A., Davies, G., Harris, S. E., Porteous, D. J., Liewald, D. C., et al. (2013). Complex variation in measures of general intelligence and cognitive change. PLoS One, 8(12), e81189.

    Article  PubMed Central  PubMed  Google Scholar 

  • Scarr, S., & McCartney, K. (1983). How people make their own environments: a theory of genotype greater than environment effects. Child Development, 54(2), 424–435.

    CAS  PubMed  Google Scholar 

  • Schaie, K. W. (1996). Intellectual development in adulthood. In J. E. Birren & K. W. Schaie (Eds.), Handbook of the psychology of aging (4th ed., pp. 266–286). New York: Academic Press.

    Google Scholar 

  • Sham, P. (1998). Statistics in human genetics. New York: Wiley.

    Google Scholar 

  • Trzaskowski, M., Dale, P. S., & Plomin, R. (2013). No genetic influence for childhood behavior problems from DNA analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 52(10), 1048–1056. e1043.

    Article  PubMed Central  PubMed  Google Scholar 

  • van Dongen, J., & Boomsma, D. I. (2013). The evolutionary paradox and the missing heritability of schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162B(2), 122–136.

    Article  Google Scholar 

  • van Dongen, J., Slagboom, P. E., Draisma, H. H., Martin, N. G., & Boomsma, D. I. (2012). The continuing value of twin studies in the Omics Era. Nature Reviews Genetics, 13(9), 640–653.

    Article  PubMed  Google Scholar 

  • Visscher, P. M., Hill, W. G., & Wray, N. R. (2008). Heritability in the Genomics Era–concepts and misconceptions. Nature Reviews Genetics, 9(4), 255–266.

    Article  CAS  PubMed  Google Scholar 

  • Yang, J., Lee, S. H., Goddard, M. E., & Visscher, P. M. (2011). Gcta: a tool for genome-wide complex trait analysis. American Journal of Human Genetics, 88(1), 76–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang, C., & Pierce, B. L. (2014). Genetic susceptibility to accelerated cognitive decline in the US Health and Retirement Study. Neurobiology of Aging, 35(6), 1512.e1511–1512.e1518.

  • Zhang, G., Karns, R., Sun, G., Indugula, S. R., Cheng, H., Havas-Augustin, D., et al. (2012). Finding missing heritability in less significant loci and allelic heterogeneity: genetic variation in human height. PLoS One, 7(12), e51211.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zuk, O., Hechter, E., Sunyaev, S. R., & Lander, E. S. (2012). The mystery of missing heritability: genetic interactions create phantom heritability. Proceedings of the National Academy of Sciences of the United States of America, 109(4), 1193–1198.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge that this work was partially supported by the National Institute on Aging (R01 AG037985).

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Correspondence to Chandra A. Reynolds.

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Reynolds, C.A., Finkel, D. A Meta-analysis of Heritability of Cognitive Aging: Minding the “Missing Heritability” Gap. Neuropsychol Rev 25, 97–112 (2015). https://doi.org/10.1007/s11065-015-9280-2

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