Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults

IF 13 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2025-03-05 DOI:10.1002/alz.14461

Vibha Acharya, Kang-Hsien Fan, Beth E. Snitz, Mary Ganguli, Steven T. DeKosky, Oscar L. Lopez, Eleanor Feingold, M. Ilyas Kamboh

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引用次数: 0

Abstract

INTRODUCTION

Many complex traits and diseases show sex-specific biases in clinical presentation and prevalence.

METHODS

To understand sex-specific genetic architecture of cognitive decline across five cognitive domains (attention, memory, executive function, language, and visuospatial function) and global cognitive function, we performed sex-stratified genome-wide meta-analysis in 3021 older adults aged ≥ 65 years (female = 1545, male = 1476) from three prospective cohorts. Gene-based and gene-set enrichment analyses were conducted for each cognitive trait.

RESULTS

We identified a novel genome-wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (rs6851574: minor allele frequency [MAF] = 0.39, P_male = 4.10E-08, β_male = 0.19; P_interaction = 3.76E-04). We also identified a subthreshold GWS locus for decline of executive function on chromosome 12 in females near the NDUFA12 gene, involved in oxidative phosphorylation (rs11107823: MAF = 0.12, P_female = 9.35E-08, β_female = 0.28; P_interaction = 7.42E-06).

DISCUSSION

Sex-aware genetic studies can help in the identification of novel genetic loci and enhance sex-specific understanding of cognitive decline.

Highlights

Our genome-wide meta-analysis of single variants identified two new genetic associations, one in males and one in females.
The novel male association was observed with the decline of memory in the intergenic region near the RPS23P3 gene on chromosome 4. This intergenic region has previously been implicated in several brain and cognition related traits, including anatomical brain aging, brain shape, and educational attainment.
The novel female-specific association was observed with decline in executive function on chromosome 12 near the NDUFA12 gene, which is involved in oxidative phosphorylation.
Sex-stratified analyses offer sex-specific understanding of biological pathways involved in cognitive aging.

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.