Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Abstract

ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

“…It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

“…Another group studied rare variants in 7 GWAS hits but the limited sample sizes precluded any firm conclusions [108] .…”

Toward precision medicine in neurological diseases

“…Furthermore, understanding the mechanisms how neurons alter and maintain their molecular signatures during disease processing is a fundamental goal of neurological diseases. Several genes, including ABCA7 (20), BIN1 (21), CR1 (22), PLD3 (23) and PICALM (24), were revealed as the excess burden of deleterious coding mutations in AD. In the epileptic encephalopathies alone, trio sequencing has led to the identification of ALG, GABRB3, DNM1, HCN1, GRIN2A, GABRA1, GNAO1, KCNT1, SCN2A, SCN8A, and SLC35A2 as genes associated with epilepsy while many of the proteins encoded by these genes are involved in synaptic transmission (8).…”