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Association of Gene Variants of the Renin-Angiotensin System With Accelerated Hippocampal Volume Loss and Cognitive Decline in Old Age
Anthony S. Zannas, M.D., M.Sc.; Douglas R. McQuoid, M.P.H.; Martha E. Payne, Ph.D., M.P.H.; James R. MacFall, Ph.D., M.S.; Allison Ashley-Koch, Ph.D.; David C. Steffens, M.D., M.H.Sc.; Guy G. Potter, Ph.D.; Warren D. Taylor, M.D., M.H.Sc.
Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2014.13111543
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The authors report no financial relationships with commercial interests.

Supported by research grants R01 MH077745, R01 MH054846, and K24 MH070027.

From the Department of Psychiatry and Behavioral Sciences, the Neuropsychiatric Imaging Research Laboratory, the Department of Radiology, the Center for Human Genetics, and the Department of Medicine, Duke University Medical Center, Durham, N.C.; the Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; the Department of Psychiatry, University of Connecticut Health Sciences Center, Farmington, Conn.; and the Department of Psychiatry, Vanderbilt University Medical Center and The Geriatric Research, Education, and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tenn.

Address correspondence to Dr. Zannas (aszannas@gmail.com).

Copyright © 2014 by the American Psychiatric Association

Received November 23, 2013; Revised April 21, 2014; Accepted May 06, 2014.

Abstract

Objective  Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus.

Method  The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype.

Results  Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss.

Conclusions  Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.

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FIGURE 1. Graphic Summary of AGTR1 Single-Nucleotide Polymorphism (SNP) Associations With Accelerated Right Hippocampal Volume Loss and Episodic Memory Decline in Old Agea

a Genotype-by-time interactions are shown as arrows connecting aging and outcomes (right hippocampal volume loss and episodic memory decline) after moderation by encircled SNPs. Direct genotype effects are shown on the right side of the figure as arrows directly connecting SNPs with episodic memory decline. The encircled numbers on each arrow represent the F values and p values as estimated from the respective mixed regression models. Further details are provided in text and Table 2.

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TABLE 1.Demographic Variables and Genotype Frequencies in a Study of the Renin-Angiotensin System, Accelerated Hippocampal Volume Loss, and Cognitive Decline in Old Agea
Table Footer Note

a All continuous variables had equal variances and were tested with pooled t test, except for education, which exhibited unequal variances between the two diagnostic groups and was thus tested using Satterthwaite t test. Reported p values are two-tailed.

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TABLE 2.Longitudinal Effects of AGTR1 Single-Nucleotide Polymorphisms (SNPs) on Hippocampal Volumesa
Table Footer Note

a Analyses conducted using linear mixed-effects models. These models tested for the effect of AGTR1 SNP genotype on hippocampal volume and also examined AGTR1-by-time and AGTR1-by-APOE-by-time interactions. All models included 138 participants and controlled for sex, age, diagnostic group (depressed or nondepressed), baseline hippocampal volume, and total cerebral volume. Values in bold denote statistically significant parameters, defined as p<0.05. Reported p values are two-tailed.

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