Genome-wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes

Heritability is well documented for psychiatric disorders and cognitive abilities which are, however, complex, involving both genetic and environmental factors. Hence, it remains challenging to discover which and how genetic variations contribute to such complex traits. In this article, they propose to use mediation analysis to bridge this gap, where neuroimaging phenotypes were utilized as intermediate variables. The Philadelphia Neurodevelopmental Cohort was investigated using genome-wide association studies (GWAS) and mediation analyses. Specifically, 951 participants were included with age ranging from 8 to 21 years. Two hundred and four neuroimaging measures were extracted from structural magnetic resonance imaging scans. GWAS were conducted for each measure to evaluate the SNP-based heritability. Furthermore, mediation analyses were employed to understand the mechanisms in which genetic variants have influence on pathological behaviors implicitly through neuroimaging phenotypes, and identified SNPs that would not be detected otherwise. Our analyses found that rs10494561, located in the intron region within NMNAT2, was associated with the severity of the prodromal symptoms of psychosis implicitly, mediated through the volume of the left hemisphere of the superior frontal region (P=2.38×10^-8). The gene NMNAT2 is known to be associated with brainstem degeneration, and produce cytoplasmic enzyme which is mainly expressed in the brain. Another SNP rs2285351 was found in the intron region of gene IFT122 which may be potentially associated with human spatial orientation ability through the area of the left hemisphere of the isthmuscingulate region (P=3.70×10^-8). Hum Brain Mapp 38:4088–4097, 2017.