Evidence of selection as a cause for racial disparities in fibroproliferative disease

• Published in: PloS one Vol. 12; no. 8; p. e0182791
• Main Authors: Hellwege, Jacklyn N., Torstenson, Eric S., Russell, Shirley B., Edwards, Todd L., Velez Edwards, Digna R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.08.2017; Public Library of Science (PLoS)
• Subjects: African Continental Ancestry Group - genetics; Alleles; Atherosclerosis; Biology and Life Sciences; Connective Tissue Diseases - ethnology; Connective Tissue Diseases - genetics; Connective tissues; Databases, Genetic; Disease; Diseases; Epidemiology; European Continental Ancestry Group - genetics; Female; Fibroids; Fibrosis; Gene Frequency; Gene mapping; Genetic Predisposition to Disease; Genetics; Genome-wide association studies; Genomes; Gynecology; Health risks; Humans; Hypertension; Infections; Linkage Disequilibrium; Liver diseases; Models, Genetic; Neoplasms, Connective and Soft Tissue - ethnology; Neoplasms, Connective and Soft Tissue - genetics; Obstetrics; Pathology; People and places; Polymorphism, Single Nucleotide; Population genetics; Populations; Prevalence; Prevalence studies (Epidemiology); Pulmonary fibrosis; Quantitative Trait Loci; Racial differences; Risk; Risk Assessment; Risk factors; Scars; Selection, Genetic; Statistical analysis; Studies; Womens health; United States > US; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182791

Fibroproliferative diseases are common complex traits featuring scarring and overgrowth of connective tissue which vary widely in presentation because they affect many organ systems. Most fibroproliferative diseases are more prevalent in African-derived populations than in European populations, leading to pronounced health disparities. It is hypothesized that the increased prevalence of these diseases in African-derived populations is due to selection for pro-fibrotic alleles that are protective against helminth infections. We constructed a genetic risk score (GRS) of fibroproliferative disease risk-increasing alleles using 147 linkage disequilibrium-pruned variants identified through genome-wide association studies of seven fibroproliferative diseases with large African-European prevalence disparities. A comparison of the fibroproliferative disease GRS between 1000 Genomes Phase 3 populations detected a higher mean GRS in AFR (mean = 148 risk alleles) than EUR (mean = 136 risk alleles; T-test p-value = 1.75x10-123). To test whether differences in GRS burden are systematic and may be due to selection, we employed the quantitative trait loci (QTL) sign test. The QTL sign test result indicates that population differences in risk-increasing allele burdens at these fibroproliferative disease variants are systematic and support a model featuring selective pressure (p-value = 0.011). These observations were replicated in an independent sample and were more statistically significant (T-test p-value = 7.26x10-237, sign test p-value = 0.015). This evidence supports the role of selective pressure acting to increase frequency of fibroproliferative alleles in populations of African relative to European ancestry populations.