Peer Review #2 of "Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia (v0.2)"

In the past 15 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 2% 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.

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Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans

10.2337/figshare.12896636.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Neeraj K. Sharma ◽

Mary E. Comeau ◽

Dennis Montoya ◽

Matteo Pellegrini ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

African Americans ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Transcript Level ◽

Matsuda Index

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated CpG-regions for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; r= -0.632, P= 4.70X10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 CpG regions associated (FDR-P <0.05) with Matsuda index, SI and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

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