Practical Calling Approach for Exome Array-Based Genome-Wide Association Studies in Korean Population.
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ABSTRACT:
SUBMITTER: Park TJ
PROVIDER: S-EPMC4706946 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/aimsLung function is an objective indicator of diagnosis and prognosis of respiratory diseases. Many common genetic variants have been associated with lung function in multiple ethnic populations. We looked for coding variants associated with forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC) in the Korean general population.MethodsWe carried out exome array analysis and lung function measurements of the FEV1 and FEV1/FVC in 7,524 individuals of the Korean population. We evaluated single variants with minor allele frequency greater than 0.5%. We performed look-ups for candidate coding variants associations in the UK Biobank, SpiroMeta, and CHARGE consortia.ResultsWe identified coding variants in the SMIM29 (C6orf1) (p = 1.2 × 10-5) and HMGA1 locus on chromosome 6p21, the GIT2 (p = 6.5 × 10-5) locus on chromosome 12q24, and the ARHGEF40 (p = 9.9 × 10-5) locus on chromosome 14q11 as having a significant association with lung function (FEV1). We also confirmed a previously reported association with lung function and chronic obstructive pulmonary disease in the FAM13A (p = 4.54 × 10-6) locus on chromosome 4q22, in TNXB (p = 1.30 × 10-6) and in AGER (p = 1.09 × 10-8) locus on chromosome 6p21.ConclusionOur exome array analysis identified that several protein coding variants were associated with lung function in the Korean population. Common coding variants in SMIM29 (C6orf1), HMGA1, GIT2, FAM13A, TNXB, AGER and low-frequency variant in ARHGEF40 potentially affect lung function, which warrant further study.
| S-EPMC8009153 | biostudies-literature
Project description:Genome-wide association studies (GWAS) are susceptible to bias due to population stratification (PS). The most widely used method to correct bias due to PS is principal components (PCs) analysis (PCA), but there is no objective method to guide which PCs to include as covariates. Often, the ten PCs with the highest eigenvalues are included to adjust for PS. This selection is arbitrary, and patterns of local linkage disequilibrium may affect PCA corrections. To address these limitations, we estimate genomic propensity scores based on all statistically significant PCs selected by the Tracy-Widom (TW) statistic. We compare a principal components and propensity scores (PCAPS) approach to PCA and EMMAX using simulated GWAS data under no, moderate, and severe PS. PCAPS reduced spurious genetic associations regardless of the degree of PS, resulting in odds ratio (OR) estimates closer to the true OR. We illustrate our PCAPS method using GWAS data from a study of testicular germ cell tumors. PCAPS provided a more conservative adjustment than PCA. Advantages of the PCAPS approach include reduction of bias compared to PCA, consistent selection of propensity scores to adjust for PS, the potential ability to handle outliers, and ease of implementation using existing software packages.
| S-EPMC6475581 | biostudies-literature
Project description:Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3'UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds.
| S-EPMC5688105 | biostudies-literature
Project description:Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.
| S-EPMC9558840 | biostudies-literature
Project description:To facilitate the clinical implementation of genomic medicine by next-generation sequencing, it will be critically important to obtain accurate and consistent variant calls on personal genomes. Multiple software tools for variant calling are available, but it is unclear how comparable these tools are or what their relative merits in real-world scenarios might be.We sequenced 15 exomes from four families using commercial kits (Illumina HiSeq 2000 platform and Agilent SureSelect version 2 capture kit), with approximately 120X mean coverage. We analyzed the raw data using near-default parameters with five different alignment and variant-calling pipelines (SOAP, BWA-GATK, BWA-SNVer, GNUMAP, and BWA-SAMtools). We additionally sequenced a single whole genome using the sequencing and analysis pipeline from Complete Genomics (CG), with 95% of the exome region being covered by 20 or more reads per base. Finally, we validated 919 single-nucleotide variations (SNVs) and 841 insertions and deletions (indels), including similar fractions of GATK-only, SOAP-only, and shared calls, on the MiSeq platform by amplicon sequencing with approximately 5000X mean coverage.SNV concordance between five Illumina pipelines across all 15 exomes was 57.4%, while 0.5 to 5.1% of variants were called as unique to each pipeline. Indel concordance was only 26.8% between three indel-calling pipelines, even after left-normalizing and intervalizing genomic coordinates by 20 base pairs. There were 11% of CG variants falling within targeted regions in exome sequencing that were not called by any of the Illumina-based exome analysis pipelines. Based on targeted amplicon sequencing on the MiSeq platform, 97.1%, 60.2%, and 99.1% of the GATK-only, SOAP-only and shared SNVs could be validated, but only 54.0%, 44.6%, and 78.1% of the GATK-only, SOAP-only and shared indels could be validated. Additionally, our analysis of two families (one with four individuals and the other with seven), demonstrated additional accuracy gained in variant discovery by having access to genetic data from a multi-generational family.Our results suggest that more caution should be exercised in genomic medicine settings when analyzing individual genomes, including interpreting positive and negative findings with scrutiny, especially for indels. We advocate for renewed collection and sequencing of multi-generational families to increase the overall accuracy of whole genomes.
| S-EPMC3706896 | biostudies-literature
Project description:To investigate exome-wide genetic variants associated with prostate cancer (PCa) in Koreans and evaluate the discriminative ability by the genetic risk score (GRS).We prospectively recruited 1,001 PCa cases from a tertiary hospital and conducted a case-control study including 2,641 healthy men (Stage I). Participants were analyzed using HumanExome BeadChip. For the external validation, additionally enrolled 514 PCa cases and 548 controls (independent cohort) were analyzed for the identified single nucleotide polymorphisms (SNPs) of Stage I (Stage II). The GRS was calculated as a non-weighted sum of the risk allele counts and investigated for accuracy of prediction of PCa.the mean age was 66.3 years, and the median level of prostate specific antigen (PSA) was 9.19 ng/ml in PCa cases. In Stage I, 4 loci containing 5 variants (rs1512268 on 8p21.2; rs1016343 and rs7837688 on 8q24.21; rs7501939 on 17q12, and rs2735839 on 19q13.33) were confirmed to reach exome-wide significance (p<8.3x10-7). In Stage II, the mean GRS was 4.23 ± 1.44 for the controls and 4.78 ± 1.43 for the cases. As a reference to GRS 4, GRS 6, 7 and 8 showed a statistically significant risk of PCa (OR=1.85, 2.11 and 3.34, respectively).The five variants were validated to associate with PCa in firstly performed exome-wide study in Koreans. The addition of individualized calculated GRS effectively enhanced the accuracy of prediction. These results need to be validated in future studies.
| S-EPMC5546451 | biostudies-literature
Project description:This review aims at better understanding the genetics of endometriosis. Endometriosis is a frequent feminine disease, affecting up to 10% of women, and characterized by pain and infertility. In the most accepted hypothesis, endometriosis is caused by the implantation of uterine tissue at ectopic abdominal places, originating from retrograde menses. Despite the obvious genetic complexity of the disease, analysis of sibs has allowed heritability estimation of endometriosis at ~50%. From 2010, large Genome Wide Association Studies (GWAS), aimed at identifying the genes and loci underlying this genetic determinism. Some of these loci were confirmed in other populations and replication studies, some new loci were also found through meta-analyses using pooled samples. For two loci on chromosomes 1 (near CCD42) and chromosome 9 (near CDKN2A), functional explanations of the SNP (Single Nucleotide Polymorphism) effects have been more thoroughly studied. While a handful of chromosome regions and genes have clearly been identified and statistically demonstrated as at-risk for the disease, only a small part of the heritability is explained (missing heritability). Some attempts of exome sequencing started to identify additional genes from families or populations, but are still scarce. The solution may reside inside a combined effort: increasing the size of the GWAS designs, better categorize the clinical forms of the disease before analyzing genome-wide polymorphisms, and generalizing exome sequencing ventures. We try here to provide a vision of what we have and what we should obtain to completely elucidate the genetics of this complex disease.
| S-EPMC8304276 | biostudies-literature
Project description:A large-scale, genome-wide association study was performed to identify genetic variations influencing serum bilirubin levels using 8841 Korean individuals. Significant associations were observed at UGT1A1 (rs11891311, P = 4.78 x 10(-148)) and SLCO1B3 (rs2417940, P = 1.03 x 10(-17)), which are two previously identified loci. The two single-nucleotide polymorphisms (SNPs) were replicated (rs11891311, P = 3.18 x 10(-15)) or marginally significant (rs2417940, P = 8.56 x 10(-4)) in an independent cohort of 1096 individuals. In a conditional analysis adjusted for the top UGT1A1 variant (rs11891311), another variant in UGT1A1 (rs4148323, P = 1.22 x 10(-121)) remained significant; this suggests that in UGT1A1 at least two independent genetic variations influence the bilirubin levels in the Korean population. The protein coding variant rs4148323, which is monomorphic in European-derived populations, may be specifically associated with serum bilirubin levels in Asians (P = 2.56 x 10(-70)). The SLCO1B3 variant (rs2417940, P = 1.67 x 10(-18)) remained significant in a conditional analysis for the top UGT1A1 variant. Interestingly, there were significant differences in the associated variations of SLCO1B3 between Koreans and European-derived populations. While the variant rs2417940 at intron 7 of SLCO1B3 was more significantly associated in Koreans, variants rs17680137 (P = 0.584) and rs2117032 (P = 2.76 x 10(-5)), two of the top-ranked SNPs in European-derived populations, did not reach the genome-wide significance level. Also, variants in SLCO1B1 did not reach genome-wide significance in Koreans. Our result supports the idea that there are considerable ethnic differences in genetic association of bilirubin levels between Koreans and European-derived populations.
| S-EPMC2928134 | biostudies-literature
Project description:BACKGROUND:Lead (Pb) is a ubiquitous toxic metal present in the environment that poses adverse health effects to humans. Inter-individual variation in blood Pb levels is affected by various factors, including genetic makeup. However, limited data are available on the association between genetic variation and blood Pb levels. The purpose of this study was to identify the genetic markers associated with blood Pb levels in the Korean population. METHODS:The study subjects consisted of 1,483 healthy adults with no history of occupational exposure to Pb. We measured blood Pb levels and calculated probable daily intake of Pb according to dietary data collected using 24-hour recall. We conducted exome-wide association screening using Illumina Human Exome-12v1.2 platform (n?=?500) and a replication analysis using VeraCode Goldengate assay (n?=?1,483). RESULTS:Among the 244,770 single nucleotide polymorphisms (SNPs) tested, 12 SNPs associated with blood Pb level were identified, with suggestive significance level (P?<?1?×?10-4). In the Goldengate assay for replication, three SNPs (C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671) were associated with statistically suggestively significant differences in blood Pb levels. When stratified by drinking status, a potential association of C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 with blood Pb level was observed only in drinkers. A marginally significant gene-environment interaction between ALDH2 rs671 and alcohol consumption was observed in relation to blood Pb levels. The effects of the three suggestively significant SNPs on blood Pb levels was dependent on daily calcium intake amounts. CONCLUSIONS:This exome-wide association study indicated that C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 polymorphisms are linked to blood Pb levels in the Korean population. Our results suggest that these three SNPs are involved in the determination of Pb levels in Koreans via the regulation of alcohol drinking behavior, and that their negative effects may be compensated by appropriate calcium intake.
| S-EPMC5316181 | biostudies-literature
Project description:Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
| S-EPMC4014590 | biostudies-literature