O2‐10‐04: MITOCHONDRIAL VARIANTS AND HAPLOGROUPS ASSOCIATED WITH LATE‐ONSET ALZHEIMER'S DISEASE IDENTIFIED BY WHOLE EXOME SEQUENCING

• DOI: 10.1016/j.jalz.2019.06.4508
• Publication Date: 2019-10-18T11:49:27Z
• Authors: Xiaoling Zhang; John Farrell; Congcong Zhu; Richard Mayeux; Jonathan L. Haines; Margaret A. Peric...; Gerard D. Schelle...; Kathryn L. Lunetta; Lindsay A.A. Farrer
• Keywords: Haplogroup; Exome; Minor allele frequency; Genetic Association

Numerous studies suggest that mitochondrial (MT) dysfunction is involved in Alzheimer disease (AD) pathogenesis. The Alzheimer's Disease Sequencing Project (ADSP) performed whole-exome sequencing (WES) of 5,519 AD cases and 4,917 cognitively normal elderly controls European ancestry (EA) 218 177 Caribbean Hispanic (CH) heritage. After mapping to the reference MT genome (NC_012920), variants were called using haploid mode GATK HaplotypeCaller. Low-quality, multi-allelic monomorphic excluded a QC metric based on comparison with Neuroimaging Initiative WGS dataset 1000 Genomes project. Haplogrep 2 software was used classify mtDNA hapogroups Phylotree 17. association single nucleotide (SNVs) minor allele count (MAC) ≥10 call rate≥ 0.80 (802 SNVs EA, 135 CH) haplogroups evaluated EAs CHs separately. In gene-based tests, only genes ≥2 rare (minor frequency <0.05) cumulative MAC≥10 tested. Analyses variant SCORE tests (SKAT-O) seqMeta R package, controlling for age, sex, principal components ancestry. Results meta-analyzed across ethnicities. Bonferroni-corrected thresholds determine study-wide significance (SWS) (P=6.2×10−5) (P=3.8×10−3) associations. EAs, 47 tested logistic regression. variant-level sample-level QC, 4,220 10,610 samples remained analyses. A missense SNV MT-ND4L which encodes NADH dehydrogenase subunit 4L ubiquinone oxidoreductase activity (26:10733:C:T, rs28709356, Asp88Glu, MAF=0.002) associated risk at nearly SWS level (OR=7.52; P=7.3×10−5). One finding identified MT-TI (P = 3.0×10−3). None AD. set high quality from large ADSP data. We significant MT-NDL4 gene. replication study data independent cohorts extension phase currently underway.