Transcriptome association studies of neuropsychiatric traits in African Americans implicatePRMT7in schizophrenia

Abstract

14In the past fifteen years, genome-wide association studies (GWAS) have provided novel insight into the genetic architecture of various complex traits; however, this insight has been primarily focused on populations of European descent. This emphasis on European populations has led to individuals of recent African descent being grossly underrepresented in the study of genetics. With African Americans making up less than two percent of participants in neuropsychiatric GWAS, this discrepancy is magnified in diseases such as schizophrenia and bipolar disorder. In this study, we performed GWAS and the gene-based association method PrediXcan for schizophrenia (n=2,256) and bipolar disorder (n=1,019) in African American cohorts. In our PrediXcan analyses, we identified PRMT7 (P = 5.5 × 10 −6 , local false sign rate = 0.12) as significantly associated with schizophrenia following an adaptive shrinkage multiple testing adjustment. This association with schizophrenia was confirmed in the much larger, predominantly European, Psychiatric Genomics Consortium. In addition to the PRMT7 association with schizophrenia, we identified rs10168049 (P = 1.0 × 10 −6 ) as a potential candidate locus for bipolar disorder with highly divergent allele frequencies across populations, highlighting the need for diversity in genetic studies.

Genetic architecture of schizophrenia: a review of major advancements

“…Many genetic studies have demonstrated population-specific characteristics due to differences in underlying genetic architecture and environmental exposures, highlighting the importance of investigating trait/disease heterogeneity in population genetic studies. There have been GWAS studies reported in Indian (Periyasamy et al, 2019), African American (Fiorica & Wheeler, 2019) and Latin American (Bigdeli et al, 2019) populations but, to date, large scale schizophrenia GWAS has primarily been investigated in people of European ancestry and more recently East Asian ancestries. The largest schizophrenia GWAS in individuals of East Asian ancestries reported 21 independent associations in 19 loci, which included the top three associations shared with the European studies, and an additional 14 associations compared to the previous study of Chinese ancestry (Lam et al, 2019).…”

PRMT7: A Pivotal Arginine Methyltransferase in Stem Cells and Development

“…Genome-wide association studies and PrediXcan (a genebased association method) for schizophrenia and bipolar disorder identified that PRMT7 was significantly correlated with schizophrenia. Further analysis showed that PRMT7 was highly expressed in the CA1 field of the hippocampus, and PRMT7 -/mice displayed defects in social behaviors [78]. Recent studies further revealed that PRMT7 -/-CA1 neurons exhibited HCN (hyperpolarization-activated, cyclic-nucleotide-gated) channel current dysfunction, which might be attributed to the decreased HCN protein levels mediated by SHANK3 downregulation [68,79].…”