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F1‐01‐03: Rare Deleterious and Loss‐of‐Function Variants in OPRL1 and GAS2L2 Contribute to the Risk of Late‐Onset Alzheimer’s Disease: Alzheimer’s Disease Sequencing Project Case‐Control Study
Author(s) -
Jian Xueqiu,
Bis Joshua C.,
Kunkle Brian W.,
Hamilton Kara L.,
Beecham Gary W.,
Bush William S.,
Salerno William,
Lancour Dan,
Ma Yiyi,
Chen Yuning,
DeStefano Anita L.,
Dupuis Josée,
Boerwinkle Eric,
Schellenberg Gerard D.,
Naj Adam C.,
Seshadri Sudha,
Fornage Myriam,
Farrer Lindsay A.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.273
Subject(s) - exome sequencing , genetics , disease , bonferroni correction , biology , gene , oncology , medicine , mutation , statistics , mathematics
when heterozygous and w14-fold when homozygous, as compared to homozygous epsilon 3 (ε3) carriers. Moreover, ε3 homozygosity itself confers w1.6-fold risk versus epsilon 2 (ε2) homozygotes and ε2/ε3 individuals. Despite this strong genetic liability, some APOE-ε4 carriers never develop symptomatic AD or have a very late age of onset, suggesting these resilient individuals may harbor protective alleles. Understanding the pathogenic mechanism behind such alleles holds great promise for novel therapeutic approaches. Methods: Two subsets of non-Hispanic Caucasians were selected from the Alzheimer’s Disease Sequencing Project Case-Control exome sequencing dataset: [1] APOE4 extremes (ε4 allele-carrying cases [n 1⁄4 492] with age of onset 65 years, and non-demented controls [n 1⁄4 625] with age at last assessment 75 years for ε4/ε4 individuals and 80 years for ε3/ε4 individuals) and [2] APOE3 extremes (ε3/ε3 cases [n 1⁄4 496] with age of onset 70 years and ε3/ε3 non-demented controls [n 1⁄4 2126] with age at last assessment 85 years). Sequencing data were subjected to strict quality control. Only low frequency or rare variants annotated as non-synonymous were retained. Primary association analyses were conducted using RvTest, which implements the Score test for single variant and SKAT-O for gene aggregation, adjusting for gender, principal components, sequencing center, and ε4 carrier status. Results: Single variant analyses uncovered several preliminary associations, including TREM2 Arg47His that increased AD susceptibility. Aggregation analyses identified a handful of genes demonstrating preliminary study-wide significance, including TREM2 and KRTAP19-4 in the APOE3 extremes. Our data suggest complex relationships connect variants in these genes with AD outcomes: combinations of risk, protective, and neutral variants likely drive the observed associations with altered disease susceptibility. Conclusions:Similar analyses in an independent cohort are ongoing. If replicated, our findings have pinpointed several novel genes that appear to influence AD risk in specific APOE genotype backgrounds, and suggest they could be prioritized for mechanistic studies and evaluation as novel therapeutic targets.