Genetic architecture of age-related cognitive decline in African Americans

Towfique Raj; Lori B Chibnik; Cristin McCabe; Andus Wong; Joseph M Replogle; Lei Yu; Sujuan Gao; Frederick W Unverzagt; Barbara Stranger; Jill Murrell; Lisa Barnes; Hugh C Hendrie; Tatiana Foroud; Anna Krichevsky; David A Bennett; Kathleen S Hall; Denis A Evans; Philip L De Jager

doi:10.1212/NXG.0000000000000125

Genetic architecture of age-related cognitive decline in African Americans

Neurol Genet. 2016 Dec 21;3(1):e125. doi: 10.1212/NXG.0000000000000125. eCollection 2017 Feb.

Authors

Towfique Raj¹, Lori B Chibnik¹, Cristin McCabe¹, Andus Wong¹, Joseph M Replogle¹, Lei Yu¹, Sujuan Gao¹, Frederick W Unverzagt¹, Barbara Stranger¹, Jill Murrell¹, Lisa Barnes¹, Hugh C Hendrie¹, Tatiana Foroud¹, Anna Krichevsky¹, David A Bennett¹, Kathleen S Hall¹, Denis A Evans¹, Philip L De Jager¹

Affiliation

¹ Program in Translational NeuroPsychiatric Genomics (T.R., L.B.C., J.M.R., P.L.D.J.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Center for Neurologic Disease (T.R., A.W., A.K., P.L.D.J.), Department of Neurology, and Division of Genetics (T.R., L.B.C., P.L.D.J.), Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School (T.R., L.B.C., P.L.D.J.), Boston, MA; Program in Medical and Population genetics (T.R., L.B.C., C.M., J.M.R., P.L.D.J.), The Broad Institute, Cambridge, MA; Section of Genetic Medicine (B.S.), Department of Medicine, and Institute for Genomics and Systems Biology (B.S.), University of Chicago, IL; Indiana University Center for Aging Research (H.C.H.); Department of Psychiatry (F.W.U., H.C.H., K.S.H.), Department of Biostatistics (S.G.), Indiana University School of Medicine; Department of Medical and Molecular Genetics (J.M., T.F.), Indiana University, Indianapolis; Rush Institute for Healthy Aging (D.A.V.), Department of Internal Medicine, Department of Neurology (L.B., D.A.B.), and Rush Alzheimer's Disease Center (L.Y., L.B., D.A.B.), Rush University Medical Center, Chicago, IL. T.R. is currently affiliated with Ronald M. Loeb Center for Alzheimer's Disease, Departments of Neuroscience, and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York.

Abstract

Objective: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs).

Methods: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS.

Results: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility.

Conclusions: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.

Abstract

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