Strongest Association Signal Research Articles

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495–45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13–1.18; p = 8.35 × 10−30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER−) breast cancer (lead SNP rs6864776: per-a allele OR ER− = 1.10; 95% CI 1.05–1.14; p conditional = 1.44 × 10−12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09–1.15; p conditional = 1.12 × 10−05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Identification of a haplotype associated with cholesterol deficiency and increased juvenile mortality in Holstein cattle.

Over the last decades, several genetic disorders have been discovered in cattle. However, the genetic background of disorders in calves is less reported. Recently, German cattle farmers reported on calves from specific matings with chronic diarrhea and retarded growth of unknown etiology. Affected calves did not respond to any medical treatment and died within the first months of life. These calves were underdeveloped in weight and showed progressive and severe emaciation despite of normal feed intake. Hallmark findings of the blood biochemical analysis were pronounced hypocholesterolemia and deficiency of fat-soluble vitamins. Results of the clinical and blood biochemical examination had striking similarities with findings reported in human hypobetalipoproteinemia. Postmortem examination revealed near-complete atrophy of the body fat reserves including the spinal canal and bone marrow. To identify the causal region, we performed a genome-wide association study with 9 affected and 21,077 control animals genotyped with the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA), revealing a strong association signal on BTA 11. Subsequent autozygosity mapping identified a disease-associated haplotype encompassing 1.01 Mb. The segment of extended homozygosity contains 6 transcripts, among them the gene APOB, which is causal for cholesterol disorders in humans. However, results from multi-sample variant calling of 1 affected and 47 unaffected animals did not detect any putative causal mutation. The disease-associated haplotype has an important adverse effect on calf mortality in the homozygous state when comparing survival rates of risk matings vs. non-risk matings. Blood cholesterol values of animals are significantly associated with the carrier status indicating a codominant inheritance. The frequency of the haplotype in the current Holstein population was estimated to be 4.2%. This study describes the identification and phenotypic manifestation of a new Holstein haplotype characterized by pronounced hypocholesterolemia, chronic emaciation, growth retardation, and increased mortality in young cattle, denominated as cholesterol deficiency haplotype. Our genomic investigations and phenotypic examinations provide additional evidence for a mutation within the APOB gene causing cholesterol deficiency in Holstein cattle.

Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci.

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

A rare variant in COL11A1 is strongly associated with adult height in Chinese Han population

Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies (GWASs) have identified that COL11A1 is an important susceptibility gene for human height. To determine whether the variants of COL11A1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chr1_103380393 with P value of 4.8 × 10−7. Chr1_103380393 also showed nominal significance in the validation stage (P = 1.21 × 10−6). Combined analysis of 16,738 samples strengthened the original association of chr1_103380393 with adult height (Pcombined = 3.1 × 10−8), with an increased height of 0.292sd (standard deviation) per G allele (95% CI: 0.19–0.40). There was no evidence (P = 0.843) showing that chr1_103380393 altered child height in 3688 child samples. Only the group of 12–15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.

Genome-wide association reveals the locus responsible for four-horned ruminant.

Phenotypic variability in horn characteristics, such as their size, number and shape, offers the opportunity to elucidate the molecular basis of horn development. The objective of this study was to map the genetic determinant controlling the production of four horns in two breeds, Jacob sheep and Navajo-Churro, and examine whether an eyelid abnormality occurring in the same populations is related. Genome-wide association mapping was performed using 125 animals from the two breeds that contain two- and four-horned individuals. A case-control design analysis of 570712 SNPs genotyped with the ovine HD SNP Beadchip revealed a strong association signal on sheep chromosome 2. The 10 most strongly associated SNPs were all located in a region spanning Mb positions 131.9-132.6, indicating the genetic architecture underpinning the production of four horns is likely to involve a single gene. The closest genes to the most strongly associated marker (OAR2_132568092) were MTX2 and the HOXD cluster, located approximately 93Kb and 251Kb upstream respectively. The occurrence of an eyelid malformation across both breeds was restricted to polled animals and those carrying more than two horns. This suggests the eyelid abnormality may be associated with departures from the normal developmental production of two-horned animals and that the two conditions are developmentally linked. This study demonstrated the presence of separate loci responsible for the polled and four-horned phenotypes in sheep and advanced our understanding of the complexity that underpins horn morphology in ruminants.

The Role of Upregulated APOE in Alzheimer's Disease Etiology.

The first and most firmly established genetic risk factor for sporadic late onset Alzheimer’s disease (LOAD) is the e4 allele of the apolipoprotein E (APOE) gene [1]. Carrying the APOEe4 variant significantly increases the lifetime risk for LOAD, with the number of copies present indicative of level of risk [1,2] and is associated with lower age of clinical disease onset [1,3–6]. Furthermore, genome-wide association studies (GWAS) for sporadic LOAD confirmed that APOE is the major susceptibility genomic region for the disease and reported significant associations with markers within the APOE linkage disequilibrium (LD) locus (contains APOE, TOMM40 and APOC1 genes). The strongest association signal (by wide margin) in these studies was found at the APOE LD region and no other LOAD-association in the human genome remotely approached the same level of significance [7–10]. However, the molecular mechanism underlying the reported genetic LOAD-associations with APOE LD region in general and APOEe4 haplotype in particular has yet to be discovered.

Exploring the Major Sources and Extent of Heterogeneity in a Genome‐Wide Association Meta‐Analysis

Genome-wide association (GWA) meta-analysis has become a popular approach for discovering genetic variants responsible for complex diseases. The between-study heterogeneity effect is a severe issue that may complicate the interpretation of results. Aiming to improve the interpretation of meta-analysis results, we empirically explored the extent and source of heterogeneity effect. We analyzed a previously reported GWA meta-analysis of obesity, in which over 21,000 subjects from seven individual samples were meta-analyzed. We first evaluated the extent and distribution of heterogeneity across the entire genome. We then studied the effects of several potentially confounding factors, including age, ethnicity, gender composition, study type, and genotype imputation on heterogeneity with a random-effects meta-regression model. Of the total 4,325,550 SNPs being tested, heterogeneity was moderate to very large for 25.4% of the total SNPs. Heterogeneity was more severe in SNPs with stronger association signals. Ethnicity, average age, and genotype imputation accuracy had significant effects on the heterogeneity. Exploring the effects of ethnicity can provide clues to the potential ethnic-specific effects for two loci known to affect obesity, MC4R, and MTCH2. Our analysis can help to clarify understanding of the obesity mechanism and may provide guidance for an effective design of future GWA meta-analysis.

Abstract 18374: Targeted Sequencing and Massively Parallel Reporter Assay Identify the Functional Variation Underlying the 4q25 Locus for Atrial Fibrillation

Introduction: Genome-wide association studies have identified 14 independent loci for atrial fibrillation (AF). The 4q25 locus upstream of the left-right asymmetry gene PITX2 is, by far, the strongest association signal for AF. However, as with most GWAS loci, the functional variants are noncoding, presumed to be regulatory, and remain unknown. We therefore sought to rapidly identify the functional variants at an AF locus by combining high throughput sequencing and massively parallel reporter assays. Methods and Results: We sequenced a ~750kb region encompassing the PITX2 locus in 462 individuals with early-onset AF from the MGH AF Study and 464 referents from the Framingham Heart Study. The SNP most significantly associated with AF in our sequenced sample was rs2129983, which is 140kb from PITX2 (OR=2.43, P =8.9X10 -16 ). rs2129983 is approximately 1.7kb from the most significantly associated SNP in a prior AF GWAS, rs6817105 (r 2 =0.52). From the targeted sequencing analysis, we identified 262 SNVs with a MAF >0.5% within a genomic region bounded by SNPs with an r2 greater than 0.4 with the top variant. To identify functional variants, we then utilized a massively parallel reporter assay (MPRA) in order to measure enhancer activity at each SNP across the entire AF locus. In both HL-1 and C2C12 myoblasts, MPRA identified many distinct SNP regions with differential enhancer activity. Using AF-association status as a standard, we were able to identify a series of variants that have both differential activity in either cell line tested and also a high level of association (rs17042076, rs4469143). Mechanistically, these functional SNPs are predicted to alter transcription factor binding. Conclusions: We have comprehensively identified the AF-associated variation at 4q25 and determined which of these variants are functional through differential enhancer activity. Here, in addition to identifying the causative variation for AF at 4q25, we provide a generalizable pathway for translating this work to other loci, a method that could expedite the identification of causative genetic variants at other disease loci.

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

Statistical selection strategy for risk and protective rare variants associated with complex traits.

In genetic association studies with deep sequencing data, it is a challenging statistical problem to precisely locate rare variants associated with complex diseases or traits due to the limited number of observed genetic mutations. In particular, both risk and protective rare variants can be present in the same gene or genetic region. There currently exist very few statistical methods to separate casual rare variants from noncausal variants within a disease/trait-related gene or a genetic region, while there are relatively many statistical tests to detect a phenotypic association of a group of rare variants such as a gene or a genetic region. In this article, we propose a new statistical selection strategy that is able to locate causal rare variants within the disease/trait-related gene or a genetic region. The proposed procedure is to linearly combine potential risk and protective variants in order to find the optimal combination of rare variants that can have the strongest association signal. It is also computationally very efficient since the procedure is based on forward selection. In simulation studies we demonstrate that the selection performance of the proposed procedure is more powerful than other existing methods when both risk and protective variants are present. We also applied it to the real sequencing data on the ANGPTL gene family from the Dallas Heart Study.

A GWAS Study on Liver Function Test Using eMERGE Network Participants.

IntroductionLiver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations.MethodsThe process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC).ResultsConsistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10−8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15).ConclusionsTaken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

RETRACTED: The identification of loci for polydactyly in chickens using a genome-wide association study

Polydactyly is a commonly observed limb malformation in humans and other vertebrates. The Beijing-You chicken expressing the polydactyly phenotype provides an opportunity to investigate the potential cause for polydactyly. Here we extensively exploited genetic determinants of the chicken polydactyly in a genome wide association study using over 580,000 SNPs characterized in a Beijing-You × Lohmann F1 cross, consisting of 79 animals. A total of 10 loci clustered on the short arm of chromosome 2 were identified to be significantly associated with the trait. Among the 10 significant SNPs, 7 were located in a linkage disequilibrium block of 1737kb. The strongest association signal (rs317674023, P=5.48×10(-8)) residing nearby Bone Morphogenetic Protein Receptor-Associated Molecule 1 (BRAM1) was identified in the genomic region. Our results provide insights to the genetic basis underlying chicken polydactyly and may facilitate studies of the limb malformation in humans and other species.

Genetic risk alleles associated with serologic autoimmunity in normal individuals (BA3P.113)

Abstract We screened 2628 normal individuals for antibodies binding to the mix of antigens in a human nuclear extract and identified 579 (26.05%) individuals with significant levels of IgG antibodies to self-antigens. Next, we analyzed 639 representative sera from ANA-, ANA+, ILE and SLEs on an autoantigen proteomic array, which identified 33 antigens strongly recognized by IgG autoantibodies in ANA+ group as compared to ANA- normals. Of these 33, 19 antigens were non-nuclear or cytoplasmic proteins and 14 were nuclear proteins, including known SLE associated antigens such as dsDNA and Histones. Antigen cluster analysis showed that DNA and RNA clusters are more frequent in SLE and ILE group, while matrix proteins and antiphospholipid antibodies clusters are more frequent in ANA+ normals. Next, all the individuals were genotyped with immunochip and subset by target sequencing. Quantitative genetic association test identified SNPs associated with ANA and auto-antigens. The strongest association signal was observed at HLA, where SNP rs3117103 near BTNL2, rs9268832 near HLA-DRA and rs2395252 in HLA-DQA2 gene showed strongest (10-7) association. Other signals were in/near BANK1, PTTG1 and CR1L genes. RNA sequencing analysis identified ANA risk alleles associated with up regulation of HLA-DRB1 in monocytes and BANK1 in B cells. Our data suggest that functional variations in or near HLA DRB1 and BANK1 gene may be associated with development of humoral autoimmunity in general population.

LO7 : A single subcutaneous dose of 2mg/kg or 4mg/kg of RG-101, a GalNAc-conjugated oligonucleotide with antagonist activity against MIR-122, results in significant viral load reductions in chronic hepatitis C patients

GWAS hits were validated in independent cohorts from Germany (529 cases vs. 761 controls) and Belgium (619 cases vs. 161 controls) and the results of the joint analyses combined. Genotyping was undertaken using Illumina BeadChips (Illumina Inc., San Diego, CA, USA); SNP replication was undertaken using Taqman chemistry (Applied Biosystems, Foster City, Ca, USA) on an automated platform. Results: The strongest association signal in the initial metaanalysis was observed between the rs738409 variant in PNPLA3 (Pmeta =1.17×10−28, OR=2.38 [2.08–2.69]); 102 separate variants at the PNPLA3 locus associated with genome-wide significance (Pthreshold <5×10−8). In addition, nine other independent loci provided borderline association signals (Pthreshold ≤1.1×10−5). Validation genotyping for rs738409 in PNPLA3 and lead markers for the top 10 associated regions confirmed disease association for rs738409 in PNPLA3, and for (MBOAT7: rs641738 Preplication = 1.35×10−4; Pcombined = 9.25×10−10; OR=1.63 [1.46–1.80] and TM6SF2: rs10401969 Preplication = 3.29×10−5; Pcombined = 1.73×10−8; OR=1.35 [1.25–1.44]).

A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05× 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08× 10(-43)) and HLA-DQα1 47 (p = 4.02× 10(-46)), 56, and 76 (both p = 1.84× 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73× 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39× 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10× 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

Wattles in goats are associated with the FMN1/GREM1 region on chromosome 10.

SummaryThe presence of congenital appendages (wattles) on the throat of goats is supposed to be under genetic control with a dominant mode of inheritance. Wattles contain a cartilaginous core covered with normal skin resembling early stages of extremities. To map the dominant caprine wattles (W) locus, we collected samples of 174 goats with wattles and 167 goats without wattles from nine different Swiss goat breeds. The samples were genotyped with the 53k goat SNP chip for a subsequent genome‐wide association study. We obtained a single strong association signal on chromosome 10 in a region containing functional candidate genes for limb development and outgrowth. We sequenced the whole genomes of an informative family trio containing an offspring without wattles and its heterozygous parents with wattles. In the associated goat chromosome 10 region, a total of 1055 SNPs and short indels perfectly co‐segregate with the W allele. None of the variants were perfectly associated with the phenotype after analyzing the genome sequences of eight additional goats. We speculate that the causative mutation is located in one of the numerous gaps in the current version of the goat reference sequence and/or represents a larger structural variant which influences the expression of the FMN1 and/or GREM1 genes. Also, we cannot rule out possible genetic or allelic heterogeneity. Our genetic findings support earlier assumptions that wattles are rudimentary developed extremities.

Abstract 2190: Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants

Abstract Background: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci facilitates detection of functional candidates and additional independent risk variants. Methods: We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Results: Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. However, in most regions the SNP showing the smallest P-value was correlated (r2≥0.2) with the index SNP. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22,2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We observed evidence for an additional independent association signal in 8q24 located between POU5F1B and MYC (rs28629385; minor allele frequency=0.06; per-allele odds ratio=1.37; P=7.9E-06). Conclusions: Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates for laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). Citation Format: Mengmeng Du, Shuo Jiao, Stephanie A. Rosse, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven Gallinger, Thomas J. Hudson, Sébastien Küry, Loic Le Marchand, Suzanne M. Leal, Polly A. Newcomb, Deborah A. Nickerson, John D. Potter, Martha L. Slattery, Li Hsu, Andrew T. Chan, Emily White, Sonja I. Berndt, Ulrike Peters. Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2014-2190

CKM and LILRB5 are associated with serum levels of creatine kinase.

Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.