Properties of human genes guided by their enrichment in rare and common variants

• Published in: Human mutation Vol. 39; no. 3; pp. 365 - 370
• Main Authors: Alhuzimi, Eman, Leal, Luis G., Sternberg, Michael J.E., David, Alessia
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.03.2018; John Wiley and Sons Inc
• Subjects: Brief Report; Brief Reports; Disease; Disease - genetics; Gene frequency; Genes; Genes, Essential; Genetic diversity; genetic variants; Genetic Variation; human disease; Humans; Mutation - genetics; protein coding genes; protein network; genetic variants; protein network; protein coding genes; human disease
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23377

We analyzed 563,099 common (minor allele frequency, MAF≥0.01) and rare (MAF < 0.01) genetic variants annotated in ExAC and UniProt and 26,884 disease‐causing variants from ClinVar and UniProt occurring in the coding region of 17,975 human protein‐coding genes. Three novel sets of genes were identified: those enriched in rare variants (n = 32 genes), in common variants (n = 282 genes), and in disease‐causing variants (n = 800 genes). Genes enriched in rare variants have far greater similarities in terms of biological and network properties to genes enriched in disease‐causing variants, than to genes enriched in common variants. However, in half of the genes enriched in rare variants (AOC2, MAMDC4, ANKHD1, CDC42BPB, SPAG5, TRRAP, TANC2, IQCH, USP54, SRRM2, DOPEY2, and PITPNM1), no disease‐causing variants have been identified in major, publicly available databases. Thus, genetic variants in these genes are strong candidates for disease and their identification, as part of sequencing studies, should prompt further in vitro analyses. We identified a novel set of genes enriched in rare variants and demonstrate that they share biological and network properties with genes enriched in disease‐causing variants. However, in half of these genes (AOC2, MAMDC4, ANKHD1, CDC42BPB, SPAG5, TRRAP, TANC2, IQCH, USP54, SRRM2, DOPEY2, and PITPNM1), no disease‐causing variants have been identified so far. Genetic variants in these genes are strong candidates for disease and their identification, as part of sequencing studies, should prompt further in vitro analyses.