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

Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume

<div><p>Prostate enlargement leading to clinical benign prostatic hyperplasia (BPH) is associated with metabolic dysregulation and obesity. The genetic basis of this association is unclear. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV). Participants included 876 men referred for prostate biopsy and found to be prostate cancer free. PV was measured by transrectal ultrasound. Samples were genotyped using the Illumina Cardio-MetaboChip platform. Multivariable adjusted linear regression models were used to evaluate SNPs (additive coding) in relation to natural-log transformed (log) PV. We compared SNP-PV results from biopsy-negative men to 442 men with low-grade prostate cancer with similar levels of obesity and PV. Beta-coefficients from the discovery and replication samples were then aggregated with fixed effects inverse variance weighted meta-analysis. SNP rs11736129 (near the pseudo-gene <i>LOC100131429</i>) was significantly associated with log-PV (beta: 0.16, p-value 1.16x10^-8) after adjusting for multiple testing. Other noteworthy SNPs that were nominally associated (p-value < 1x10^-4) with log-PV included rs9583484 (intronic SNP in <i>COL4A2</i>), rs10146527 (intronic SNP in <i>NRXN3</i>), rs9909466 (SNP near <i>RPL32P31</i>), and rs2241606 (synonymous SNP in <i>SLC12A7</i>). We found several SNPs in metabolic loci associated with PV. Further studies are needed to confirm our results and elucidate the mechanism between these genetic loci, PV, and clinical BPH.</p></div

Fibroproliferative diseases with increased prevalence in African-derived populations.

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

MetaboChip SNPs Nominally Associated with Natural-log Transformed Prostate Volume at p <1x10^-4 in Men without Prostate Cancer (PC) and Men with Low-grade PC: the Nashville Men’s Health Study.

<p>CHR = Chromosome; SNP = Single Nucleotide Polymorphism MA = Minor Allele; RA = Referent Allele; MAF = Minor Allele Frequency; Beta Coefficient from linear regression model evaluating natural log transformed prostate volume as a continuous dependent variable, while adjusting for age (continuous), body mass index (continuous), height (continuous), and 10 genetic ancestry principal components.</p><p>*SNP is on the gene; but is on the intron region</p><p>MetaboChip SNPs Nominally Associated with Natural-log Transformed Prostate Volume at p <1x10^-4 in Men without Prostate Cancer (PC) and Men with Low-grade PC: the Nashville Men’s Health Study.</p

Enriched pathways for module genes by Ingenuity Pathway Analysis.

<p><i>P</i> values adjusted by Benjamini & Hochberg (BH) method <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002587#pcbi.1002587-Benjamini1" target="_blank">[33]</a>.</p

Genetic Determinants of Prostate Volume at p<1x10^-4 from Meta-analysis Combining Results across Diagnostic Groups: the Nashville Men’s Health Study.

<p>CHR = Chromosome; SNP = Single Nucleotide Polymorphism MA = Minor Allele; RA = Referent Allele; MAF = Minor Allele Frequency; I² = amount of heterogeneity between groups not explained due to chance; Table sorted by Fixed effects P value;</p><p>*SNP is on the intron region of the gene</p><p>**SNP is on the exon region of the gene</p><p>Genetic Determinants of Prostate Volume at p<1x10^-4 from Meta-analysis Combining Results across Diagnostic Groups: the Nashville Men’s Health Study.</p

Materials and MethodscMaterials and Methodsgenes for schizophrenia.

<p>Materials and MethodscMaterials and Methodsgenes for schizophrenia.</p