Population-based genome-wide association study of cognitive decline in older adults free of dementia: identification of a novel locus for the attention domain

M Ilyas Kamboh; Kang-Hsien Fan; Qi Yan; Joanne C Beer; Beth E Snitz; Xingbin Wang; Chung-Chou H Chang; F Yesim Demirci; Eleanor Feingold; Mary Ganguli

doi:10.1016/j.neurobiolaging.2019.02.024

Population-based genome-wide association study of cognitive decline in older adults free of dementia: identification of a novel locus for the attention domain

Neurobiol Aging. 2019 Dec:84:239.e15-239.e24. doi: 10.1016/j.neurobiolaging.2019.02.024. Epub 2019 Mar 11.

Authors

Affiliations

¹ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: kamboh@pitt.edu.
² Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

PMID: 30954325
PMCID: PMC6739197
DOI: 10.1016/j.neurobiolaging.2019.02.024

Abstract

To identify novel loci that affect cognitive decline in older adults free of dementia, we conducted genome-wide and gene-based meta-analyses on longitudinal slopes of 5 cognitive domains (memory, executive function, language, attention/processing speed, and visuospatial ability) derived from 2 population-based cohorts. For decline over time in each cognitive domain, we normalized intraindividual slopes within each cohort, accounting for baseline age, sex, and years of education. Normalized slope for each domain was used in cohort-specific genome-wide analyses after including top principal components as covariates followed by genome-wide and gene-based meta-analyses. Both analyses revealed a novel WDFY2 locus at genome-wide (p = 3.37E-08) and gene-wide (p = 7.10E-07) significance levels for the attention/processing speed domain. In the GTEx eQTL analysis, genome-wide significant single-nucleotide polymorphism was associated with RNA expression levels of WDFY2 in several brain regions: cerebellar hemisphere (p = 1.07E-04), cerebellum (p = 6.92E-04), hippocampus (p = 2.18E-03) and cortex (p = 2.29E-02), and in whole blood (p = 4.41E-05). Our results suggest that WDFY2 genetic variation may affect individual differences in decline over time on tests of attention/processing speed.

Keywords: Cognitive decline; Cognitive domains; Gene-based association; Genome-wide association.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aged
Aged, 80 and over
Attention
Cognitive Dysfunction / genetics*
Dementia
Genome-Wide Association Study*
Humans

Abstract

Publication types

MeSH terms

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