Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by <i>APOE</i> Genotype
Authors: Yiyi Ma, Gyungah R. Jun, Xiaoling Zhang, Jaeyoon Chung, Adam C. Naj, Yuning Chen, Celine Bellenguez, Kara Hamilton-Nelson, Eden R. Martin, Brian W. Kunkle, Joshua C. Bis, Stéphanie Debette, Anita L. DeStefano, Myriam Fornage, Gaël Nicolas, Cornelia van Duijn, David A. Bennett, Philip L. De Jager, Richard Mayeux, Jonathan L Haines, Margaret A. Pericak-Vance, Sudha Seshadri, Jean-Charles Lambert, Gerard D. Schellenberg, Kathryn L. Lunetta, Lindsay A. Farrer
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular<i>APOE</i>alleles. <h3>Objective</h3> To identify<i>APOE</i>genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. <h3>Design, Setting, and Participants</h3> The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. <h3>Main Outcomes and Measures</h3> Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of<i>APOE</i>ε4 carriers and noncarriers. Results with<i>P</i> ≤ 1 × 10<sup>−5</sup>were further evaluated in the replication data sets and combined by meta-analysis. <h3>Results</h3> Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample withrs536940594inAC099552(odds ratio [OR], 88.0; 95% CI, 9.08-852.0;<i>P</i> = 2.22 × 10<sup>−7</sup>) andrs138412600in<i>GPAA1</i>(OR, 1.78; 95% CI, 1.44-2.2; meta-<i>P</i> = 7.81 × 10<sup>−8</sup>).<i>GPAA1</i>was also associated with expression in the brain of<i>GPAA1</i>(β = −0.08;<i>P</i> = .03) and its repressive transcription factor,<i>FOXG1</i>(β = 0.13;<i>P</i> = .003), and global cognition function (β = −0.53;<i>P</i> = .009). Significant gene-wide associations (threshold<i>P</i> ≤ 6.35 × 10<sup>−7</sup>) were observed for<i>OR8G5</i>(<i>P</i> = 4.67 × 10<sup>−7</sup>),<i>IGHV3-7</i>(<i>P</i> = 9.75 × 10<sup>−16</sup>), and<i>SLC24A3</i>(<i>P</i> = 2.67 × 10<sup>−12</sup>) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). <h3>Conclusions and Relevance</h3> The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without<i>APOE</i>ε4 alleles that reinforce known and suggest additional pathways leading to AD.