Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for GNG4 and KCNQ2 Genes.

Luke W Bonham, Daniel S Evans, Yongmei Liu, Steven R Cummings, Kristine Yaffe, Jennifer S Yokoyama

Journal: American journal of Alzheimer's disease and other dementias 2019;33(3):153-165

PMID: 29338302

Abstract

BACKGROUND/RATIONALE

Experimental studies support the role of neurotransmitter genes in dementia risk, but human studies utilizing single variants in candidate genes have had limited success.

METHODS

We used the gene-based testing program Versatile Gene-based Association Study to assess whether aggregate variation across 6 neurotransmitter pathways influences risk of cognitive decline in 8159 cognitively normal elderly (≥65 years old) adults from 3 community-based cohorts.

RESULTS

Common genetic variation in GNG4 and KCNQ2 was associated with cognitive decline. In human brain tissue data sets, both GNG4 and KCNQ2 show higher expression in hippocampus relative to other brain regions; GNG4 expression decreases with advancing age. Both GNG4 and KCNQ2 show highest expression in fetal astrocytes.

CONCLUSION

Genetic variation analyses and gene expression data suggest that GNG4 and KCNQ2 may be associated with cognitive decline in normal aging. Gene-based testing of neurotransmitter pathways may confirm and reveal novel risk genes in future studies of healthy cognitive aging.

Address: 1 Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.; 2 California Pacific Medical Center Research Institute, San Francisco, CA, USA.; 3 Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.; 4 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.; 5 Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.; 6 Department of Psychiatry, University of California, San Francisco, CA, USA.

DOI: 10.1177/1533317517739384

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MeSH Terms: Aged, Aging, Alzheimer Disease, Brain, Cognitive Dysfunction, Female, GTP-Binding Protein gamma Subunits, Genetic Association Studies, Hippocampus, Humans, KCNQ2 Potassium Channel, Male, Neurotransmitter Agents