Atlas of human diseases influenced by genetic variants with extreme allele frequency differences

Abstract

Genetic variants with extreme allele frequency differences (EAFD) may underlie some human health disparities across populations. To identify EAFD loci, we systematically analyzed and characterized 81 million genomic variants from 2504 unrelated individuals of 26 world populations (phase III of the 1000 Genomes Project). Our analyses revealed a total of 434 genes, 15 pathways, and 18 diseases and traits influenced by EAFD variants from five continental populations. They included known EAFD genes, such as LCT (lactose tolerance), SLC24A5 (skin pigmentation), and EDAR (hair morphology). We found many novel EAFD genes, including TBC1D2B (autophagy mediator), TRIM40 (gastrointestinal inflammatory regulator), KRT71, KRT75, KRT83, and KRTAP10-1 (hair and epithelial keratin synthesis), PIK3R3 (insulin receptor interaction), DARS (neurological disorders), and NACA2 (skin inflammatory response). Our results also showed four complex diseases significantly associated with EAFD loci, including asthma (adjusted enrichment P = 4 × 10−8), type I diabetes (P = 6 × 10−9), alcohol consumption (P = 0.0002), and attention deficit/hyperactivity disorder (P = 0.003). This study provides a comprehensive atlas of genes, pathways, and human diseases significantly influenced by EAFD variants.

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Acknowledgments

This work was supported by the Start-up Fund of The University of Vermont to D. Li. The data used in this study were from the 1000 Genomes Project (Phase 3), the KEGG database, the GWAS Catalog (November 13th, 2015), and annotation databases of VEP and ANNOVAR. We would like to thank Dr. Gonçalo Abecasis and Dr. Adam Auton for providing us with the gene-wide PBS statistics information. We are grateful to Dr. Xun Chen and Guangchen Liu for their critical comments and feedback throughout the process of preparing this manuscript. We thank reviewers for their constructive comments.

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Correspondence to Dawei Li.

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Sulovari, A., Chen, Y.H., Hudziak, J.J. et al. Atlas of human diseases influenced by genetic variants with extreme allele frequency differences. Hum Genet 136, 39–54 (2017). https://doi.org/10.1007/s00439-016-1734-y

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Keywords

  • Rare Variant
  • Population Pair
  • Continental Group
  • GWAS Catalog
  • Derive Allele Frequency