Medical Records-Based Genetic Studies of the Complement System

2021 ◽  
pp. ASN.2020091371
Author(s):  
Atlas Khan ◽  
Ning Shang ◽  
Lynn Petukhova ◽  
Jun Zhang ◽  
Yufeng Shen ◽  
...  
Keyword(s):  
Electronic Medical Records ◽  
Complement Activation ◽  
Genetic Variants ◽  
Medical Records ◽  
Kidney Diseases ◽  
Association Studies ◽  
Structural Genomic ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

BackgroundGenetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.MethodsWe performed medical records–based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.ResultsIn a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; β=0.20; 95% CI, 0.14 to 0.25; P=1.52x10-11) and chr.19p13.3 (C3 locus; rs11569470-G; β=0.19; 95% CI, 0.13 to 0.24; P=1.29x10-8). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; β=0.40; 95% CI, 0.34 to 0.45; P=4.58x10-35). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (β=−0.36; 95% CI, −0.42 to −0.30; P=2.98x10-22) and C4-AL-BS (β=0.25; 95% CI, 0.21 to 0.29; P=8.11x10-23). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation.ConclusionsWe discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

2021 ◽  
pp. ASN.2020111599
Author(s):  
Zhi Yu ◽  
Jin Jin ◽  
Adrienne Tin ◽  
Anna Köttgen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Diseases ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Plasma Proteome ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy

2019 ◽  
Vol 40 (5) ◽  
pp. 661-668 ◽  
Author(s):  
Asahi Hishida ◽  
Tomotaka Ugai ◽  
Ryosuke Fujii ◽  
Masahiro Nakatochi ◽  
Michael C Wu ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Gastric Atrophy ◽  
Stage I ◽  
Cancer Center ◽  
Genome Wide Association Studies ◽  
Genetic Traits ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Abstract Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10−7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10−8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10−27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

Abstract P225: African American LDL-C GWAS Reveals a Strong Protective SNP Association in APOE; The eMERGE Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Laura J Rasmussen-Torvik ◽  
Jennifer A Pacheco ◽  
M G Hayes ◽  
Abel N Kho ◽  
Arun Muthalagu ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Electronic Medical Records ◽  
Effect Size ◽  
Medical Records ◽  
Association Studies ◽  
Genetic Research ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Several Genome-Wide Association Studies (GWAS) of LDL-C have been published in populations of European-Ancestry but only one previous GWAS of LDL-C has been published in African Americans. Using phenotype data extracted from repeated lab measurements of LDL-C in electronic medical records (EMR) and the Illumina 1M Duo array we performed a LDL-C GWAS in African Americans in the eMERGE study. Methods: African Americans from eMERGE sites Northwestern University and Vanderbilt University were included in the analysis. All available LDL-C measurements as well as information about statin and hormone prescriptions, cancer, diabetes, and hypo/hyperthyroidism were abstracted from electronic medical records. Two separate samples were created; a sample incorporating exclusions due to medication use and disease diagnoses (n = 618) and a sample without exclusions (n = 1249). After data extraction and cleaning, median LDL-C for each individual was used for both analyses. GWAS analysis of median LDL-C was conducted using PLINK, controlling for age, age2, sex, recruitment site, genotyping batch, and the first three principal components of ancestry. Results: One SNP was significantly (p < 5 X 10-8) associated with LDL-C in both samples; rs7412 in the APOE gene. In the sample excluding measurements taken from those on medication or with prevalent disease, the effect size of this association was large compared to SNPs identified in previous GWAS results for LDL-C (a decrease of 19.9 mg/dl per one additional copy of the minor allele, p = 8.7 x 10 -11). The percent of LDL-C variance accounted for by rs7412 in this sample was 6.7%. The effect size of the rs7412 association was smaller in the sample without exclusions (a decrease of 12.3 mg/dl in LDL-C per allele, p = 1.6 x 10 -9) but still large compared to other LDL-C GWAS findings. Effect sizes for SNPs previously identified in the other African American GWAS of LDL-C were consistent with the earlier report, although there was not sufficient power for these associations to achieve genome-wide significance in this population. Discussion: SNP rs7412 appears to be an important common genetic variant influencing LDL-C levels. Although other signals in APOE have been detected in previous GWAS of European-Ancestry populations and African Americans and this specific SNP has been reported in several previous candidate gene studies, this association has not been identified previously in GWAS likely because rs7412 (or a good proxy) was not included on the genotyping arrays used in these studies. Our results (a) indicate that the association of rs7412 and LDL-C should be examined in other larger African American study populations, (b) further validate the use if EMR-derived traits in genetic research and (c) suggest one should be cautious in concluding that currently published GWAS have discovered all important common genetic variation contributing to certain disease traits.

scholarly journals A Genome-Wide Association Study Identifies the Association between the 12q24 Locus and Black Tea Consumption in Japanese Populations

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3182
Author(s):  
Kyohei Furukawa ◽  
Maki Igarashi ◽  
Huijuan Jia ◽  
Shun Nogawa ◽  
Kaoru Kawafune ◽  
...  
Keyword(s):  
Alcohol Drinking ◽  
Genetic Variants ◽  
Association Studies ◽  
Black Tea ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Tea Consumption ◽  
Genome Wide ◽  
A Genome ◽  
Drinking Frequency

Several genome-wide association studies (GWASs) have reported the association between genetic variants and the habitual consumption of foods and drinks; however, no association data are available regarding the consumption of black tea. The present study aimed to identify genetic variants associated with black tea consumption in 12,258 Japanese participants. Data on black tea consumption were collected by a self-administered questionnaire, and genotype data were obtained from a single nucleotide polymorphism array. In the discovery GWAS, two loci met suggestive significance (p < 1.0 × 10−6). Three genetic variants (rs2074356, rs144504271, and rs12231737) at 12q24 locus were also significantly associated with black tea consumption in the replication stage (p < 0.05) and during the meta-analysis (p < 5.0 × 10−8). The association of rs2074356 with black tea consumption was slightly attenuated by the additional adjustment for alcohol drinking frequency. In conclusion, genetic variants at the 12q24 locus were associated with black tea consumption in Japanese populations, and the association is at least partly mediated by alcohol drinking frequency.

scholarly journals Five genetic variants explain over 70% of hair coat pheomelanin intensity variation in purebred and mixed breed domestic dogs

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250579
Author(s):  
Andrea J. Slavney ◽  
Takeshi Kawakami ◽  
Meghan K. Jensen ◽  
Thomas C. Nelson ◽  
Aaron J. Sams ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Full Range ◽  
Intensity Variation ◽  
Domestic Dogs ◽  
Validation Dataset ◽  
Data Set ◽  
Genome Wide ◽  
A Genome ◽  
Mixed Breed ◽  
Wide Range

In mammals, the pigment molecule pheomelanin confers red and yellow color to hair, and the intensity of this coloration is caused by variation in the amount of pheomelanin. Domestic dogs exhibit a wide range of pheomelanin intensity, ranging from the white coat of the Samoyed to the deep red coat of the Irish Setter. While several genetic variants have been associated with specific coat intensity phenotypes in certain dog breeds, they do not explain the majority of phenotypic variation across breeds. In order to gain further insight into the extent of multigenicity and epistatic interactions underlying coat pheomelanin intensity in dogs, we leveraged a large dataset obtained via a direct-to-consumer canine genetic testing service. This consisted of genome-wide single nucleotide polymorphism (SNP) genotype data and owner-provided photos for 3,057 pheomelanic mixed breed and purebred dogs from 63 breeds and varieties spanning the full range of canine coat pheomelanin intensity. We first performed a genome-wide association study (GWAS) on 2,149 of these dogs to search for additional genetic variants that underlie intensity variation. GWAS identified five loci significantly associated with intensity, of which two (CFA15 29.8 Mb and CFA20 55.8 Mb) replicate previous findings and three (CFA2 74.7 Mb, CFA18 12.9 Mb, CFA21 10.9 Mb) have not previously been reported. In order to assess the combined predictive power of these loci across dog breeds, we used our GWAS data set to fit a linear model, which explained over 70% of variation in coat pheomelanin intensity in an independent validation dataset of 908 dogs. These results introduce three novel pheomelanin intensity loci, and further demonstrate the multigenic nature of coat pheomelanin intensity determination in domestic dogs.

scholarly journals A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

2021 ◽  
Vol 12 ◽  
Author(s):  
Hye-Won Cho ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Genetic Variants ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Fat Distribution ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

scholarly journals A Genome-Wide Association Study of spontaneous preterm birth in a European population

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 255 ◽  
Author(s):  
Wilfred Wu ◽  
Erin A S Clark ◽  
Tracy A Manuck ◽  
M Sean Esplin ◽  
Michael W Varner ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Genetic Variants ◽  
Association Studies ◽  
European Population ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Spontaneous Preterm Birth ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Background: Preterm birth is defined as a birth prior to 37 completed weeks’ gestation. It affects more than 10% of all births worldwide, and is the leading cause of neonatal mortality in non-anomalous newborns. Even if the preterm newborn survives, there is an increased risk of lifelong morbidity. Despite the magnitude of this public health problem, the etiology of spontaneous preterm birth is not well understood. Previous studies suggest that genetics is an important contributing factor. We therefore employed a genome-wide association approach to explore possible fetal genetic variants that may be associated with spontaneous preterm birth.Methods: We obtained preterm birth phenotype and genotype data from the National Center for Biotechnology Information Genotypes and Phenotypes Database (study accession phs000103.v1.p1). This dataset contains participants collected by the Danish National Birth Cohort and includes 1000 preterm births and 1000 term births as controls. Whole genomes were genotyped on the Illumina Human660W-Quad_v1_A platform, which contains more than 500,000 markers. After data quality control, we performed genome-wide association studies for the 22 autosomal chromosomes.Results: No single nucleotide polymorphism reached genome-wide significance after Bonferroni correction for multiple testing.Conclusion: We found no evidence of genetic association with spontaneous preterm birth in this European population. Approaches that facilitate detection of both common and rare genetic variants, such as evaluation of high-risk pedigrees and genome sequencing, may be more successful in identifying genes associated with spontaneous preterm birth.

scholarly journals GENOME-WIDE ASSOCIATION STUDY OF EXTREME HUMAN LONGEVITY DISCOVERS UNCOMMON LONGEVITY VARIANTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S209-S209
Author(s):  
Anastasia Gurinovich ◽  
Anastasia Gurinovich ◽  
Zeyuan Song ◽  
Stacy L Andersen ◽  
Thomas T Perls ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Human Longevity ◽  
Mixed Effect ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract The strong heritability of extreme human longevity supports the hypothesis that this is a genetically-regulated trait. However, association studies focused on common genetic variants have discovered a limited number of longevity-associated genes. We conducted a genome-wide association study of 4,216 individuals including 1317 centenarians from the New England Centenarian Study (median age = 104 years) using &gt;9M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The set included approximately 5M uncommon variants. The associations were tested using a mixed effect logistic regression model with genotype-based kinship covariance of the random effects to adjust for cryptic relations using the package GENESIS. The analysis discovered 45 genome-wide significant SNPs (p&lt; 5E-08) including 8 new loci in chromosomes 3, 6, 7, 9, 10, 14 and 15 in addition to the APOE locus. The list includes new pQTLs in serum that suggest a new biological mechanism involved in extreme human longevity.

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