A statistical method for image-mediated association studies discovers genes and pathways associated with four brain disorders

• Published in: American journal of human genetics Vol. 111; no. 1; pp. 48 - 69
• Main Authors: He, Jingni, Antonyan, Lilit, Zhu, Harold, Ardila, Karen, Li, Qing, Enoma, David, Zhang, William, Liu, Andy, Chekouo, Thierry, Cao, Bo, MacDonald, M. Ethan, Arnold, Paul D., Long, Quan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2024; Elsevier
• Subjects: Brain Diseases - genetics; cerebellum; Genetic Predisposition to Disease; Genome-Wide Association Study - methods; GWAS; Humans; image-derived phenotypes; image-mediated association study; neuropsychiatric disorders; Phenotype; Polymorphism, Single Nucleotide - genetics; Quantitative Trait Loci - genetics; image-derived phenotypes; neuropsychiatric disorders; image-mediated association study; GWAS; cerebellum
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2023.11.006

Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. By leveraging the UK Biobank image-derived phenotypes (IDPs), the IMAS discovered genetic bases underlying four neuropsychiatric disorders and verified them by analyzing annotations, pathways, and expression quantitative trait loci (eQTLs). A cerebellar-mediated mechanism was identified to be common to the four disorders. Simulations show that, if the goal is identifying genetic risk, our IMAS is more powerful than a hypothetical protocol in which the imaging results were available in the GWAS dataset. This implies the feasibility of reanalyzing legacy GWAS datasets without conducting additional imaging, yielding cost savings for integrated analysis of genetics and imaging. The authors developed a computational tool, the image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. A cerebellar-mediated mechanism was identified to be common to the four disorders.