Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

Abstract

Introduction African Americans’ (AAs) late-onset Alzheimer’s disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. Methods We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. Results Two SNPs at novel loci, rs112404845 (P = 3.8 × 10−8), upstream of COBL, and rs16961023 (P = 4.6 × 10−8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. Discussion An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Targeted Sequencing of Alzheimer Disease Genes in African Americans Implicates Novel Risk Variants

“…Extensions of these findings and the contributions of additional loci have emerged from investigations of non-EA cohorts, African Americans (AAs) in particular (Reitz et al, 2013a; Mez et al, 2017). The risk of AD is greater in AAs than EAs, however, paradoxically, 𝜀4 has a weaker effect in AAs than EAs (Farrer et al, 1997; Reitz et al, 2013a).…”

Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

“…Proposed environmental risk factors include a history of head trauma [2][3][4] and infection [5][6][7]. In recent years, large-scale genome-wide association studies (GWAS) and family-based studies have made considerable progress in defining the genetic component of AD risk, and >30 AD risk loci have been identified [8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

“…Although the prevalence of the characteristic plaques and neurofibrillary tangles was reported not to differ between African Americans and Caucasians with AD [19][20][21], a more recent study described increased AD-associated neuropathology in African Americans [22]. Further, there are now four late-onset AD risk genes identified for African Americans from genome-wide association studies and one of those gene variants is found only in African Americans [23,24]. Such studies indicate the advantage of using different approaches to understanding what is likely to be a complex picture of AD-related ethnicity differences.…”