Transferability of genome-wide associated loci for asthma in African Americans

<p><i>Objective:</i> Transferability of significantly associated loci or GWAS “hits” adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. <i>Methods:</i> Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an “exact” approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a “local” approach that examined all the regional SNPs in LD with the index SNP. <i>Results:</i> Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], <i>P</i> = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149–4.013], <i>P</i> = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected <i>P</i> values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of <i>IL33</i> were significantly associated with asthma. <i>Conclusions:</i> This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the <i>IL33</i>, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding.</p

Multiple Loci Associated with Renal Function in African Americans

<div><p>The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in <em>APOL1</em> associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry <em>vs</em>. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.</p> </div

Association with eGFR stratified by ancestry.

a<p>Positions are based on NCBI build 36.</p>b<p>Shown are the nominal numbers of SNPs in the set for each locus.</p>c<p>“DoF” indicates the effective degrees of freedom for each locus, which is the correction factor used to adjust <i>p</i>-values.</p>d<p>β_meta and SE_meta refer to the estimates from the meta-analysis combined across the three strata of local ancestry.</p

Characteristics of the study sample.

a<p>Ranges are presented as median (first quartile, third quartile).</p

Common and rare exonic <i>MUC5B</i> variants associated with type 2 diabetes in Han Chinese

<div><p>Genome-wide association studies have identified over one hundred common genetic risk variants associated with type 2 diabetes (T2D). However, most of the heritability of T2D has not been accounted for. In this study, we investigated the contribution of rare and common variants to T2D susceptibility by analyzing exome array data in 1,908 Han Chinese genotyped with Affymetrix Axiom® Exome Genotyping Arrays. Based on the joint common and rare variants analysis of 57,704 autosomal SNPs within 12,244 genes using Sequence Kernel Association Tests (SKAT), we identified significant associations between T2D and 25 variants (9 rare and 16 common) in <i>MUC5B</i>, <i>p</i>-value 1.01×10⁻¹⁴. This finding was replicated (p = 0.0463) in an independent sample that included 10,401 unrelated individuals. Sixty-six of 1,553 possible haplotypes based on 25 SNPs within <i>MUC5B</i> showed significant association with T2D (Bonferroni corrected p values < 3.2×10⁻⁵). The expression level of <i>MUC5B</i> is significantly higher in pancreatic tissues of persons with T2D compared to those without T2D (p-value = 5×10⁻⁵). Our findings suggest that dysregulated MUC5B expression may be involved in the pathogenesis of T2D. As a strong candidate gene for T2D, <i>MUC5B</i> may play an important role in the mechanisms underlying T2D etiology and its complications.</p></div

Exome Array Association Results.

<p>The y axis represents the–log₁₀ (p-value) and the x axis is variant positions by chromosome. Genome-wide and suggestive statistical significance thresholds are illustrated by the two dotted lines.</p

<i>MUC5B</i> differential expression in pancreatic islets from T2D and non-T2D organ donors.

<p>Displayed on the y axis are the mean and standard deviation values of log₂ transformation of expression data.</p

Allele Counts by type 2 diabetes status for variants in the <i>MUC5B and ABCC12 genes</i>.

<p>Allele Counts by type 2 diabetes status for variants in the <i>MUC5B and ABCC12 genes</i>.</p

Haplotypes association results across <i>MUC5B</i>.

<p>the y axis represents–log₁₀ (p values) and the x axis shows position within <i>MUC5B</i>. Red dotted lines indicate the Bonferroni correction level (-log₁₀ (0.05/1,553)), Points above the line are odds ratio values > 1, and below are odds ratio values < 1. Green dotted lines indicate the positions of significantly associated SNPs in single SNPs analyses. The “*” symbol by the SNP label indicates rare variants (MAF ≤ 0.0162). The LD heat map presents pairwise r² values within <i>MUC5B</i> based on the CADM study.</p

Top results for the joint association analyses of common and rare exome variants with T2D in Han Chinese individuals.

<p>Top results for the joint association analyses of common and rare exome variants with T2D in Han Chinese individuals.</p