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

The Alzheimer's Disease Sequencing Project (ADSP) is a US Presidential Initiative to identify novel genes, specifically rare genetic variants involved in determining risk of late-onset AD (LOAD). In the Discovery Phase individuals of European or Caribbean Hispanic ancestry were whole-exome sequenced. 10,835 unrelated LOAD cases (N = 5,740; mean age = 76) and controls (N = 5,095; mean age = 86) with approximately 1.6 million SNVs and 50,000 indels passed quality control. The two ethnic groups were analyzed separately and the results were combined by meta-analysis using the seqMeta R package. Associations with AD status were tested using both individual variant-based (score test) and gene-based tests (SKAT-O), adjusting for age, sex, and principal components, with or without adjustment for APOE genotype. For gene-based tests, annotation-based criteria were applied to group low-frequency and rare variants (MAF < 0.05). Statistical significance was evaluated after Bonferroni correction for the number of tests performed. The single variant tests identified several SNVs within known AD risk genes including APOE, TREM2, and ABCA7. Gene-based tests revealed two novel genes. By grouping deleterious variants within each gene, opiate receptor-like 1 (OPRL1, p = 6.55x10-6) reached exome-wide significance. This gene had four predicted damaging missense SNVs, among which rs148484121 (MAF = 0.003, p = 5.86x10-6) was the most significant association. OPRL1 encodes a G protein-coupled receptor that is involved in a variety of brain functions such as memory, thinking and behavior. By grouping loss-of-function variants within each gene, growth-arrest-specific 2-like 2 (GAS2L2, p = 6.02x10-6) reached exome-wide significance in the APOE-adjusted analysis. This gene had two frameshift indels and the most significant association was for rs587633197 (MAF = 0.0007, p = 6.11x10-5). GAS2L2 encodes a protein that may modulate neuronal functions by interacting with the adenosine A2a receptor, and it is strongly expressed in some gliomas. Whole exome sequencing analysis of ADSP case-control data replicated several known AD genes and identified two novel associations. A follow-up study in independent samples is underway to replicate these findings. Functional studies are warranted to uncover the biological pathways implicated.