Association between the ENPP1 K121Q Polymorphism and Risk of Diabetic Kidney Disease: A Systematic Review and Meta-Analysis

The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I^² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.     

Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.     

Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations

MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log₁₀(Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log₁₀(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology.     

Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10⁻⁴ in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.     

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10⁻⁹⁴<P<5×10⁻⁸, odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2×10⁻²³ < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.     

Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10⁻¹⁷, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10⁻⁶, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10⁻³, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.     

Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10^-09; rs12008279—OR 1.56, P = 1.53 x 10^-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10^-09; rs6622126—OR 1.75, P = 4.04x10^-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10^-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10^-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.     

Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians

Autoimmune thyroid diseases (AITD) are multifactorial endocrine diseases most frequently accompanied by Tg and TPO autoantibodies. Both antibodies have a higher prevalence in females and act under a strong genetic influence.To identify novel variants underlying thyroid antibody levels, we performed GWAS meta-analysis on the plasma levels of TgAb and TPOAb in three Croatian cohorts, as well as gender specific GWAS and a bivariate analysis.No significant association was detected with the level of TgAb and TPOAb in the meta-analysis of GWAS or bivariate results for all individuals. The bivariate analysis in females only revealed a genome-wide significant association for the locus near GRIN3A (rs4457391, P = 7.76 × 10^?9). The same locus had borderline association with TPOAb levels in females (rs1935377, P = 8.58 × 10^?8).In conclusion, we identified a novel gender specific locus associated with TgAb and TPOAb levels. Our findings provide a novel insight into genetic and gender differences associated with thyroid antibodies.     

Genome-wide association studies of the PR interval in African Americans

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10⁻⁸) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10⁻²³). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.     

Caucasian and Asian specific rheumatoid arthritis risk loci reveal limited replication and apparent allelic heterogeneity in north Indians

Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker.Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p = 3×10⁻³); IL2–21 (rs13119723, p = 0.008); HLA-DRB1 (rs660895, p = 2.56×10⁻⁵; rs6457617, p = 1.6×10⁻⁰⁹; rs13192471, p = 6.7×10⁻¹⁶); TNFA1P3 (rs9321637, p = 0.03); CCL21 (rs13293020, p = 0.01); IL2RA (rs2104286, p = 1.9×10⁻⁴) and ZEB1 (rs2793108, p = 0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ∼50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.     

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10⁻⁸). SNP rs7560163 (P = 7.0×10⁻⁹, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10⁻⁵) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.     

Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10⁻³), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10⁻⁴) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10⁻⁷), was without significant heterogeneity between ancestries (P_het = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.     

Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10^-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10^-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10^-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.     

Association of CD247 Polymorphisms with Rheumatoid Arthritis: A Replication Study and a Meta-Analysis

Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87–0.93, P_overall = 2.1×10⁻¹⁰). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk.     

Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10^-7). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10^-7. Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.     

Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.     

MHC region and risk of systemic lupus erythematosus in African American women

The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case–control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 × 10⁻⁵) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 × 10⁻⁴), rs2071349 (OR = 1.53, p = 1.0 × 10⁻³), and rs2844580 (OR = 1.43, p = 1.3 × 10⁻³), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.     

Fine Mapping of the Body Fat QTL on Human Chromosome 1q43

IntroductionEvidence for linkage and association of obesity-related quantitative traits to chromosome 1q43 has been reported in the Quebec Family Study (QFS) and in populations of Caribbean Hispanic ancestries yet no specific candidate locus has been replicated to date.MethodsUsing a set of 1,902 single nucleotide polymorphisms (SNPs) genotyped in 525 African American (AA) and 391 European American (EA) women enrolled in the NIEHS uterine fibroid study (NIEHS-UFS), we generated a fine association map for the body mass index (BMI) across a 2.3 megabase-long interval delimited by RGS7 (regulator of G-protein signaling 7) and PLD5 (Phospholipase D, member 5). Multivariable-adjusted linear regression models were fitted to the data to evaluate the association in race-stratified analyses and meta-analysis.ResultsThe strongest associations were observed in a recessive genetic model and peaked in the 3’ end of RGS7 at intronic rs261802 variant in the AA group (p = 1.0 x 10⁻⁴) and in meta-analysis of AA and EA samples (p = 9.0 x 10⁻⁵). In the EA group, moderate associations peaked at rs6429264 (p = 2.0 x 10⁻³) in the 2 Kb upstream sequence of RGS7. In the reference populations for the European ancestry in the 1,000 genomes project, rs6429264 occurs in strong linkage disequilibrium (D’ = 0.94) with rs1341467, the strongest candidate SNP for total body fat in QFS that failed genotyping in the present study. Additionally we report moderate associations at the 3’ end of PLD5 in meta-analysis (3.2 x 10⁻⁴ ≤ p ≤ 5.8 x 10⁻⁴).ConclusionWe report replication data suggesting that RGS7, a gene abundantly expressed in the brain, might be a putative body fat QTL on human chromosome 1q43. Future genetic and functional studies are required to substantiate our observations and to potentially link them to the neurobehavioral phenotypes associated with the RGS7 region.     

Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10⁻¹². No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.     

Contribution of Common PCSK1 Genetic Variants to Obesity in 8,359 Subjects from Multi-Ethnic American Population

Common PCSK1 variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common PCSK1 variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (P = 0.006) and obesity (P = 0.018) but also increased the obesity incidence during the 20 years of follow-up (HR = 1.53 [1.07–2.19], P = 0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (P = 0.028) and obesity (P = 0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR = 1.23 [1.05–1.45], P = 9.5×10⁻³). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (P = 4.2×10⁻³) and obesity (P = 3.4×10⁻³) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (P = 0.756 and P = 0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full PCSK1 locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings.