Feasibility and application of polygenic score analysis to the morphology of human-induced pluripotent stem cells

Genome-wide association studies have identified thousands of significant associations between genetic variants and complex traits. Inferring biological insights from these associations has been challenging. One approach attempted has been to examine the effects of individual variants in cellular models. Here, I demonstrate the feasibility of examining the aggregate effect of many variants on cellular phenotypes. I examine the effects of polygenic scores for cross-psychiatric disorder risk, schizophrenia, body mass index and height on cellular morphology, using 1.5 million induced pluripotent stem cells (iPSC) from 60 European-ancestry donors from the Human iPSC Initiative dataset. I show that measuring multiple cells per donor provides sufficient power for polygenic score analyses, and that cross-psychiatric disorder risk is associated with cell area (p = 0.004). Combined with emerging methods of high-throughput iPSC phenotyping, cellular polygenic scoring is a promising method for understanding potential biological effects of the polygenic component of complex traits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00438-022-01905-2.