A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores

More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10 ). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10 ) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10 ). GRN (rs5848, P = 4.21 × 10 ) and PURG (rs117523305, P = 1.73 × 10 ) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10 ) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10 ) and PTPRD (rs145989094, P = 8.34 × 10 ) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10 ) and PTPRD (rs145989094, P = 3.85 × 10 ) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors o