Summary: Researchers have identified two genetic risk factors for Alzheimer’s disease in African Americans.
Source: Boston University Medical Center.
New research has uncovered two genetic risk loci associated with late-onset Alzheimer’s disease (AD) in African Americans.
Published online in Alzheimer’s & Dementia, the study pinpoints variants near the genes COBL and SLC10A2 and highlights a statistical approach that improves the power of genome-wide analyses in understudied populations. These findings may guide the development of targeted therapies that address genetic contributors to AD risk in African Americans.
Although African Americans experience higher rates of Alzheimer’s disease compared with non-Hispanic whites, the genetic landscape that influences AD risk in African Americans has been less thoroughly characterized. To date, researchers have identified more than 20 AD risk genes in primarily European ancestry cohorts, while fewer than five loci have been consistently reported for African American populations. This study narrows that gap by identifying two novel loci that reach genome-wide significance in an African American cohort.
The investigators reanalyzed data from a previously published genome-wide association study (GWAS) that included more than 5,500 African American participants. Instead of genotyping new samples or recruiting additional volunteers, the team improved statistical power by incorporating clinical and lifestyle covariates—such as age, sex, diabetes status, smoking status, and educational attainment—into their genetic association model. This informed conditioning approach derives a posterior liability score that accounts for known risk factors and then tests single-nucleotide polymorphisms (SNPs) for association with that score.
Using this method in 1,825 late-onset AD cases and 3,784 cognitively normal controls, the authors identified two SNPs that reached genome-wide significance: rs112404845 upstream of COBL and rs16961023 downstream of SLC10A2. The study controlled for previously reported loci, including APOE and ABCA7, demonstrating that the new signals are independent of those established risk factors.
The study’s corresponding author, Jesse Mez, MD, MS, assistant professor of neurology at Boston University School of Medicine and associate director of the Boston University Alzheimer’s Disease & CTE Center Clinical Core, emphasized the translational potential: genes that increase AD risk may serve as druggable targets for disease-modifying therapies. COBL and SLC10A2 represent promising candidates for further functional investigation and therapeutic exploration.
By leveraging existing genotype data and augmenting statistical models with relevant clinical variables, the researchers were able to detect associations that standard GWAS approaches had missed. This efficient strategy reduces the need for immediate additional genotyping or large new recruitment efforts and could be applied to other diseases and underrepresented populations to accelerate genetic discovery.
Addressing the imbalance in genetic research across ancestral groups is essential for equitable advances in precision medicine. The authors hope this work helps close the knowledge gap about Alzheimer’s risk in African Americans and that the loci they’ve identified will inform future research into disease mechanisms and targeted treatments.
Source: Gina DiGravio, Boston University Medical Center
Image Source: NeuroscienceNews.com image in the public domain.
Original Research: Mez J., Chung J., Jun G., et al. “Two novel loci, COBL and SLC10A2, for Alzheimer’s disease in African Americans.” Alzheimer’s & Dementia. Published online October 19, 2016. doi:10.1016/j.jalz.2016.09.002
Boston University Medical Center (2016). Study Identifies Two New Genes Responsible for Alzheimer’s in African Americans. NeuroscienceNews. October 25, 2016.
Abstract
Two novel loci, COBL and SLC10A2, for Alzheimer’s disease in African Americans
Introduction
The genetic risk profile for late-onset Alzheimer’s disease (LOAD) in African Americans remains incompletely characterized. Incorporating clinical covariates into genetic analyses through informed conditioning may enhance the ability to detect disease-associated loci.
Methods
The authors performed a GWAS in African Americans using an informed conditioning approach in 1,825 LOAD cases and 3,784 cognitively normal controls. They derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, using external prevalence estimates to inform parameters. The association between that posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs) was evaluated while controlling for known LOAD loci such as APOE and ABCA7.
Results
Two SNPs at novel loci demonstrated genome-wide significant association with the posterior liability: rs112404845 (P = 3.8 × 10−8) upstream of COBL and rs16961023 (P = 4.6 × 10−8) downstream of SLC10A2.
Discussion
The informed conditioning approach enabled detection of genetic associations for LOAD in African Americans that were not identified by traditional GWAS methods. These findings expand understanding of AD genetics in an understudied population and suggest new targets for follow-up functional studies.