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

Abstract

The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p<8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

Identifying Rare Variant Associations in Admixed Populations

“…These sample sizes are realistic in that they reflect the scales of recent deep sequencing studies in African Americans. For example, 489 Alzheimer’s cases and 472 controls were sequenced a target sequencing study on Alzheimer’s disease 51 . The Jackson Heart Study 52 has deeply sequenced more than 3400 African Americans.…”

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

“…An independent African American case–control study, however, could not replicate the association, with a carrier frequency of 9.2% in patients and 7.4% in controls. Differences in cohort ancestry between studies could be a potential explanation for this discrepancy [76].…”

“…Numerous independent studies reported this observation in 2015, including hypothesis-free studies such as a large-scale imputation study [77] and a small exome-array association study [78], as well as targeted gene resequencing studies [71, 79]. Particularly rare PTC variants, comprising frameshift variants, nonsense variants, and variants causing out-of-frame splicing, were highly enriched in AD [80, 81, 75, 71, 82, 83, 72, 76, 84–86, 77, 79].…”

“…Thirteen published studies have examined the associations of ABCA7 PTC variants in AD–control cohorts [80, 81, 75, 71, 82, 83, 72, 76, 84–86, 77, 79]. All, but one, observed a higher frequency of heterozygous PTC variants in patients than controls; yet a large range of ORs is reported varying from approximately 1.4 [76] to 5 [85] in studies reporting an enrichment in patients. This relatively low 1.4 OR was reported in a study conducted on an African American cohort [76], and was mostly driven by a substantially weaker risk effect for common African American PTC p.Arg578 fs than its originally reported effect size (Table 1).…”

Presence of recombination hotspots throughout SLC6A3

“…To clarify these possibilities, it is necessary to deeply sequence the regulatory regions for a better understanding of the SLC6A3 genetic structure including the 3’ VNTRs, given the implications of SLC6A3 in a spectrum of diseases and other behavioral characteristics. This task requires systemic discovery of polymorphisms and haplotypes in the regulatory regions, through targeted deep-sequencing that is helpful in discovery of novel functional loci or mutations in different fields[62–69]. In other words, the presence of multiple SLC6A3 regulatory regions mandates mechanistic studies of the SLC6A3 genetics, to help delineating functionally distinct SLC6A3 haplotypes.…”