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Schick U.M.,Fred Hutchinson Cancer Research Center | Auer P.L.,Fred Hutchinson Cancer Research Center | Auer P.L.,University of Wisconsin - Milwaukee | Bis J.C.,University of Washington | And 47 more authors.
Human Molecular Genetics | Year: 2015

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that isassociated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ~25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency 5 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10-6). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10-15). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-∈2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10-8), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In genebased tests, a burden of rare/lower frequency variation inCRPin EAs (P ≤ 6.8 × 10-4) and in retinoic acid receptor-related orphan receptor a (RORA) in AAs (P = 1.7 × 10-3) were associated with CRP levels at the candidate gene level (P < 2.0 × 10-3). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels. © The Author 2014.


Udler M.S.,Massachusetts General Hospital | Nadkarni G.N.,Massachusetts General Hospital | Wyatt C.,Massachusetts General Hospital | Bottinger E.P.,Massachusetts General Hospital | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2015

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P 1x1027). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR,45 ml/min per 1.73 m2, and ESRD, with effects increasing with worsening disease states and the contribution of genetic African ancestry decreasing in parallel. Using genetic ancestry in the eGFR equation to reclassify patients as black on the basis of 50%African ancestry resulted in higher eGFR for 14.7% of Hispanic/Latino Americans and lower eGFR for 4.1% of African Americans, affecting CKD staging in 4.3% and 1% of participants, respectively. Reclassified individuals had electrolyte values consistentwith their newly assignedCKDstage. In summary, proportion of African ancestry was significantly associated with normal-range creatinine and eGFR, whereas APOL1 risk haplotypes drove the associations with CKD. Recalculation of eGFR on the basis of genetic ancestry affected CKD staging and warrants additional investigation. Copyright © 2015 by the American Society of Nephrology.


PubMed | University of Turku, Ohio State University, University of Cologne, The Charles Bronfman Institute for Personalized Medicine and and 65 more.
Type: | Journal: Journal of the American Society of Nephrology : JASN | Year: 2016

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (n


PubMed | Human Genetics Center, Baylor College of Medicine, University of Verona, University of Pennsylvania and 20 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in 25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P 6.8 10(-4)) and in retinoic acid receptor-related orphan receptor (RORA) in AAs (P = 1.7 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.


PubMed | Karolinska Institutet, University Utrecht, St George's, University of London, Stanford University and 8 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between 2.4 million (Stage 1) or 200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the VErsatile Gene-based Association Study (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 10(-6) for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity.

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