Abstract
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.
Highlights
Fibroproliferative diseases are a consequence of dysregulated scarring and connective tissue overgrowth, affect many organ systems, vary widely in presentation, and are very common in humans[1, 2]
This study sought to determine whether allele frequency differences at known fibroproliferative risk loci are consistent with evidence for selective pressure and may explain racial disparities associated with fibroproliferative diseases through evaluating loci implicated by genome wide association studies (GWAS)
A genetic risk score (GRS) utilizing single nucleotide polymorphisms (SNPs) from the Genome-wide association studies (GWAS) catalog [19] was constructed for seven fibroproliferative diseases with increased prevalence (>2 fold on average) in African ancestry populations compared to European ancestry populations (Table 1)
Summary
Fibroproliferative diseases are a consequence of dysregulated scarring and connective tissue overgrowth, affect many organ systems, vary widely in presentation, and are very common in humans[1, 2]. Keloid scars, pulmonary fibrosis, cirrhosis, Crohn’s disease, and atherosclerosis are examples of diseases with fibroproliferative features. Many fibroproliferative diseases are more prevalent in recently African-derived populations than in European populations[3], collectively contributing to pronounced overall health disparity (Table 1). Selection and racial disparities in fibroproliferative diseases
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