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

<div><p>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.</p></div

Distribution of fibroproliferative disease GRS in populations from 1000 Genomes.

<p>Results are sorted by median risk allele burden. Bars represent the 25^th and 75^th percentiles and are color coded by super-population (Green = EUR, Blue = AMR, Orange = SAS, Purple = EAS, Red = AFR).</p

Summary statistics for fibroproliferative GRS among AFR and EUR populations from 1000 Genomes, and among BioVU samples.

<p>Summary statistics for fibroproliferative GRS among AFR and EUR populations from 1000 Genomes, and among BioVU samples.</p

Cumulative distribution of GRS in 1000 Genomes AFR, EUR, ASW, and BioVU populations.

<p>*AFR includes only the continental African populations.</p

Fibroproliferative diseases with increased prevalence in African-derived populations.

<p>Fibroproliferative diseases with increased prevalence in African-derived populations.</p

Regional association plots for SNP x BMI (continuous) interaction p-values for targeted region in chromosome 6 before and after meta-analysis with European American women.

<p>Plotted p-values are for BMI x SNP interaction term in the following scenarios: a) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA; b) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA + BIOVU EA.</p

Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.

<p>Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.</p

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids

<div><p>Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10^-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10^-5) around <i>ADTRP</i> (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10^-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10^-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes <i>COL5A2</i>, and <i>TFPI</i>, an immediate downstream target of <i>ADTRP</i>. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.</p></div

Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.

<p>Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.</p

Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.

<p>Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.</p