The phenotypic indicators included: (1) EduYears and EduAge for EA, (2) household income and Townsend deprivation index (TDI) for SES and (3) seven cognitive tests. Genome-wide CNV-level and gene-level association analysis was performed by PLINK. For the identified genes, protein-protein interaction network and biological knowledgebases were utilized to decipher their functions. Finally, a phenome-wide association study was performed for each significant CNV to clarify their clinical phenotypic profiles and impact on brain structure.
Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31 and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb) and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders.