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GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

ABSTRACT: Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated.To assess these GWA findings in 4 large data sets of families affected by AD.Follow-up of genetic association findings in previous studies.Academic research.More than 4000 DNA samples from almost 1300 families affected with AD.Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods.In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P =.002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets.GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population.

SUBMITTER: Schjeide BM

PROVIDER: S-EPMC2841135 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

Schjeide Brit-Maren M BM Hooli Basavaraj B Parkinson Michele M Hogan Meghan F MF DiVito Jason J Mullin Kristina K Blacker Deborah D Tanzi Rudolph E RE Bertram Lars L

Archives of neurology 20090201 2

<h4>Background</h4>Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated.<h4>Objective</h4>To assess these GWA findings in 4 large data sets of families affected by AD.<h4>Design</h4>Follow-up of genetic association findings in previous studies.<h4>Setting</h4>Academic research.<h4>Participa ...[more]

PMID: 19204163

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Project description:Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10-10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.

Dataset Information

GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

Publications

GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

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