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Population Genetics
Polygenic Risk Score Identifies Subgroup with Higher Burden of Atherosclerosis and Greater Relative Benefit from Statin Therapy in the Primary Prevention Setting
Feb 22, 2017   Circulation
Natarajan P, Young R, Stitziel NO, Padmanabhan S, Baber U, Mehran R, Sartori S, Fuster V, Reilly DF, Butterworth AS, Rader DJ, Ford I, Sattar N, Kathiresan S
Ancient X chromosomes reveal contrasting sex bias in Neolithic and Bronze Age Eurasian migrations
Feb 22, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Goldberg A, Günther T, Rosenberg NA, Jakobsson M
Ancient X chromosomes reveal contrasting sex bias in Neolithic and Bronze Age Eurasian migrations
Feb 22, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
UNASSIGNED: Dramatic events in human prehistory, such as the spread of agriculture to Europe from Anatolia and the late Neolithic/Bronze Age migration from the Pontic-Caspian Steppe, can be investigated using patterns of genetic variation among the people who lived in those times. In particular, studies of differing female and male demographic histories on the basis of ancient genomes can provide information about complexities of social structures and cultural interactions in prehistoric populations. We use a mechanistic admixture model to compare the sex-specifically-inherited X chromosome with the autosomes in 20 early Neolithic and 16 late Neolithic/Bronze Age human remains. Contrary to previous hypotheses suggested by the patrilocality of many agricultural populations, we find no evidence of sex-biased admixture during the migration that spread farming across Europe during the early Neolithic. For later migrations from the Pontic Steppe during the late Neolithic/Bronze Age, however, we estimate a dramatic male bias, with approximately five to 14 migrating males for every migrating female. We find evidence of ongoing, primarily male, migration from the steppe to central Europe over a period of multiple generations, with a level of sex bias that excludes a pulse migration during a single generation. The contrasting patterns of sex-specific migration during these two migrations suggest a view of differing cultural histories in which the Neolithic transition was driven by mass migration of both males and females in roughly equal numbers, perhaps whole families, whereas the later Bronze Age migration and cultural shift were instead driven by male migration, potentially connected to new technology and conquest.
Natural variation and dosage of the HEI10 meiotic E3 ligase control
Feb 22, 2017   Genes & Development
Ziolkowski PA, Underwood CJ, Lambing C, Martinez-Garcia M, Lawrence EJ, Ziolkowska L, Griffin C, Choi K, Franklin FC, Martienssen RA, Henderson IR
Natural variation and dosage of the HEI10 meiotic E3 ligase control
Feb 22, 2017
Genes & Development
UNASSIGNED: During meiosis, homologous chromosomes undergo crossover recombination, which creates genetic diversity and balances homolog segregation. Despite these critical functions, crossover frequency varies extensively within and between species. Although natural crossover recombination modifier loci have been detected in plants, causal genes have remained elusive. Using natural © 2017 Ziolkowski et al.; Published by Cold Spring Harbor Laboratory Press.
Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in cattle
Feb 22, 2017   Genetics, Selection, Evolution : GSE
Pausch H, MacLeod IM, Fries R, Emmerling R, Bowman PJ, Daetwyler HD, Goddard ME
Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in cattle
Feb 22, 2017
Genetics, Selection, Evolution : GSE
BACKGROUND: The availability of dense genotypes and whole-genome sequence variants from various sources offers the opportunity to compile large datasets consisting of tens of thousands of individuals with genotypes at millions of polymorphic sites that may enhance the power of genomic analyses. The imputation of missing genotypes ensures that all individuals have genotypes for a shared set of variants. RESULTS: We evaluated the accuracy of imputation from dense genotypes to whole-genome sequence variants in 249 Fleckvieh and 450 Holstein cattle using Minimac and FImpute. The sequence variants of a subset of the animals were reduced to the variants that were included on the Illumina BovineHD genotyping array and subsequently inferred in silico using either within- or multi-breed reference populations. The accuracy of imputation varied considerably across chromosomes and dropped at regions where the bovine genome contains segmental duplications. Depending on the imputation strategy, the correlation between imputed and true genotypes ranged from 0.898 to 0.952. The accuracy of imputation was higher with Minimac than FImpute particularly for variants with a low minor allele frequency. Using a multi-breed reference population increased the accuracy of imputation, particularly when FImpute was used to infer genotypes. When the sequence variants were imputed using Minimac, the true genotypes were more correlated to predicted allele dosages than best-guess genotypes. The computing costs to impute 23,256,743 sequence variants in 6958 animals were ten-fold higher with Minimac than FImpute. Association studies with imputed sequence variants revealed seven quantitative trait loci (QTL) for milk fat percentage. Two causal mutations in the DGAT1 and GHR genes were the most significantly associated variants at two QTL on chromosomes 14 and 20 when Minimac was used to infer genotypes. CONCLUSIONS: The population-based imputation of millions of sequence variants in large cohorts is computationally feasible and provides accurate genotypes. However, the accuracy of imputation is low in regions where the genome contains large segmental duplications or the coverage with array-derived single nucleotide polymorphisms is poor. Using a reference population that includes individuals from many breeds increases the accuracy of imputation particularly at low-frequency variants. Considering allele dosages rather than best-guess genotypes as explanatory variables is advantageous to detect causal mutations in association studies with imputed sequence variants.
HLA Amino Acid Polymorphisms and Kidney Allograft Survival
Feb 21, 2017   Transplantation
Kamoun M, McCullough KP, Maiers M, Fernandez Vina MA, Li H, Teal V, Leichtman AB, Merion RM
HLA Amino Acid Polymorphisms and Kidney Allograft Survival
Feb 21, 2017
Transplantation
BACKGROUND: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid mismatches at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those mismatches assessed at the antigenic (2-digit) specificity. METHODS: Data on 240,024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding amino acid polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen mismatches. RESULTS: We show that estimated amino acid mismatches at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen mismatches with graft survival. A statistically significant linear relationship between the estimated number of amino acid mismatches and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months following transplantation (HR = 1.30 per 15 DRB1 amino acid MM; P< 0.0001). CONCLUSIONS: This study shows that independent of the well-known association of HLA antigen (2-digit specificity) mismatches with kidney graft survival, estimated amino acid mismatches at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of graft failure.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Serum magnesium and the risk of prediabetes: a population-based cohort study
Feb 22, 2017   Diabetologia
Kieboom BC, Ligthart S, Dehghan A, Kurstjens S, de Baaij JH, Franco OH, Hofman A, Zietse R, Stricker BH, Hoorn EJ
Serum magnesium and the risk of prediabetes: a population-based cohort study
Feb 22, 2017
Diabetologia
AIMS/HYPOTHESIS: Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk. METHODS: Within the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR). RESULTS: A total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantly influenced diabetes risk (p 
Accurate eQTL prioritization with an ensemble-based framework
Feb 22, 2017   Human Mutation
Zeng H, Edwards MD, Guo Y, Gifford DK
Accurate eQTL prioritization with an ensemble-based framework
Feb 22, 2017
Human Mutation
UNASSIGNED: We present a novel ensemble-based computational framework, EnsembleExpr, that achieved the best performance in the Fourth Critical Assessment of Genome Interpretation (CAGI4) "eQTL-causal SNPs" challenge for identifying eQTLs and prioritizing their gene expression effects. Expression quantitative trait loci (eQTLs) are genome sequence variants that result in gene expression changes and thus are prime suspects in the search for contributions to the causality of complex traits. When EnsembleExpr is trained on data from massively parallel reporter assays (MPRA) it accurately predicts reporter expression levels from unseen regulatory sequences and identifies sequence variants that exhibit significant changes in reporter expression. Compared with other state-of-the-art methods, EnsembleExpr achieved competitive performance when applied on eQTL datasets determined by other protocols. We envision EnsembleExpr to be a resource to help interpret non-coding regulatory variants and prioritize disease-associated mutations for downstream validation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Assessment of calcium and zinc accumulation in cultivated and wild apples
Feb 24, 2017   Journal Of The Science Of Food And Agriculture
Liao L, Fang T, Ma B, Deng X, Zhao L, Han Y
Assessment of calcium and zinc accumulation in cultivated and wild apples
Feb 24, 2017
Journal Of The Science Of Food And Agriculture
BACKGROUND: Apple is one of the staple fruits worldwide, which are a good source of mineral nutrients. However, little is known about genetic variation for mineral nutrition in apple germplasm. In this study, we report on the assessment of calcium and zinc contents in mature fruits of 378 apple cultivars and 39 wild relatives. Mineral concentrations were quantified using flame atomic absorption spectroscopy (FAAS). RESULTS: Both calcium and zinc accumulation showed great variation among accessions tested. Overall, wild fruits were significantly richer in zinc than cultivated fruits, whilst the average concentration of calcium was similar between cultivated and wild fruits. The difference in zinc concentration between wild and cultivated fruits may be an indirect result of artificial selection on fruit characteristics during apple domestication. Moreover, calcium concentration in fruit showed a decrease trend throughout fruit development of apple, whilst zinc concentration in fruit displayed a complex variation pattern in the late stages of fruit development. CONCULSION: The finding of a wild genetic variation for fruit calcium and zinc accumulation in apple germaplsm could be helpful for future research on genetic dissection and improvement of calcium and zinc accumulation in apple fruit. This article is protected by copyright. All rights reserved.
Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study
Feb 23, 2017   Menopause (New York, N.Y.)
Crandall CJ, Manson JE, Hohensee C, Horvath S, Wactawski-Wende J, LeBlanc ES, Vitolins MZ, Nassir R, Sinsheimer JS
Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study
Feb 23, 2017
Menopause (New York, N.Y.)
OBJECTIVE: Vasomotor symptoms (VMS, ie, hot flashes or night sweats) are reported by many, but not all, women. The extent to which VMS are genetically determined is unknown. We evaluated the relationship of genetic variation and VMS. METHODS: In this observational study, we accessed data from three genome-wide association studies (GWAS) (SNP Health Association Resource cohort [SHARe], WHI Memory Study cohort [WHIMS+], and Genome-Wide Association Studies of Treatment Response in Randomized Clinical Trials [GARNET] studies, total n = 17,695) of European American, African American, and Hispanic American postmenopausal women aged 50 to 79 years at baseline in the Women's Health Initiative Study. We examined genetic variation in relation to VMS (yes/no) in each study and using trans-ethnic inverse variance fixed-effects meta-analysis. A total of 11,078,977 single-nucleotide polymorphisms (SNPs) met the quality criteria. RESULTS: After adjustment for covariates and population structure, three SNPs (on chromosomes 3 and 11) were associated with VMS at the genome-wide threshold of 5 × 10 in the African American SHARe GWAS, but were not associated in the other cohorts. In the meta-analysis, 14 SNPs, all located on chromosome 4 in the tachykinin receptor 3 (TACR3) locus, however, had P < 5 × 10. These SNPs' effect sizes were similar across studies/participants' ancestry (odds ratio ∼1.5). CONCLUSIONS: Genetic variation in TACR3 may contribute to the risk of VMS. To our knowledge, this is the first GWAS to examine SNPs associated with VMS. These results support the biological hypothesis of a role for TACR3 in VMS, which was previously hypothesized from animal and human studies. Further study of these variants may lead to new insights into the biological pathways involved in VMS, which are poorly understood.
Impact of Genetic Variation on Human CaMKK2 Regulation by Ca
Feb 23, 2017   Scientific Reports
O'Brien MT, Oakhill JS, Ling NX, Langendorf CG, Hoque A, Dite TA, Means AR, Kemp BE, Scott JW
Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome
Feb 23, 2017   Human Mutation
Carlston CM, O'Donnell-Luria AH, Underhill HR, Cummings BB, Weisburd B, Minikel EV, Birnbaum DP, Exome Aggregation Consortium, Tvrdik T, MacArthur DG, Mao R
Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome
Feb 23, 2017
Human Mutation
The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a six-year-old female patient with seizures, developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like Bohring-Opitz syndrome have reduced penetrance, or the misclassification of potentially pathogenic variants. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Predicting gene expression in massively parallel reporter assays: a comparative study
Feb 21, 2017   Human Mutation
Kreimer A, Zeng H, Edwards MD, Guo Y, Tian K,   . . . . . .   , Kundaje A, Beer MA, Keles S, Gifford DK, Yosef N
Predicting gene expression in massively parallel reporter assays: a comparative study
Feb 21, 2017
Human Mutation
UNASSIGNED: In many human diseases, associated genetic changes tend to occur within non-coding regions, whose effect might be related to transcriptional control. A central goal in human genetics is to understand the function of such non-coding regions: Given a region that is statistically associated with changes in gene expression (expression Quantitative Trait Locus; eQTL), does it in fact play a regulatory role? And if so, how is this role "coded" in its sequence? These questions were the subject of the Critical Assessment of Genome Interpretation eQTL challenge. Participants were given a set of sequences that flank eQTLs in humans and were asked to predict whether these are capable of regulating transcription (as evaluated by massively parallel reporter assays), and whether this capability changes between alternative alleles. Here, we report lessons learned from this community effort. By inspecting predictive properties in isolation, and conducting meta-analysis over the competing methods, we find that using chromatin accessibility and transcription factor binding as features in an ensemble of classifiers or regression models leads to the most accurate results. We then characterize the loci that are harder to predict, putting the spotlight on areas of weakness, which we expect to be the subject of future studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome
Feb 21, 2017   Translational Research : The Journal Of Laboratory And Clinical Medicine
Guénard F, Tchernof A, Deshaies Y, Biron S, Lescelleur O, Biertho L, Marceau S, Pérusse L, Vohl MC
Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome
Feb 21, 2017
Translational Research : The Journal Of Laboratory And Clinical Medicine
UNASSIGNED: A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P 
gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels
Feb 17, 2017   Genetic Epidemiology
Larson NB, McDonnell S, Cannon Albright L, Teerlink C, Stanford J,   . . . . . .   , Ackerman MJ, Olson TM, Klein CJ, Thibodeau SN, Schaid DJ
gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels
Feb 17, 2017
Genetic Epidemiology
UNASSIGNED: Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results. © 2017 WILEY PERIODICALS, INC.
Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
Feb 18, 2017   Circulation. Cardiovascular Genetics
Hedman ÅK, Mendelson MM, Marioni RE, Gustafsson S, Joehanes R,   . . . . . .   , Arnett DK, Deary IJ, Lind L, Levy D, Ingelsson E
Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
Feb 18, 2017
Circulation. Cardiovascular Genetics
BACKGROUND: Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. METHODS AND RESULTS: To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage ( CONCLUSIONS: We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. © 2017 The Authors.
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
Feb 17, 2017   Journal Of The American College Of Cardiology
Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NG,   . . . . . .   , Samani NJ, Schunkert H, Deloukas P, Kathiresan S, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
Feb 17, 2017
Journal Of The American College Of Cardiology
Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NG, Jansen H, Kanoni S, Nelson CP, Ferrario PG, König IR, Eicher JD, Johnson AD, Hamby SE, Betsholtz C, Ruusalepp A, Franzén O, Schadt EE, Björkegren JL, Weeke PE, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, Goel A, Farrall M, Peloso GM, Won HH, Do R, van Iperen E, Kruppa J, Mahajan A, Scott RA, Willenborg C, Braund PS, van Capelleveen JC, Doney AS, Donnelly LA, Asselta R, Merlini PA, Duga S, Marziliano N, Denny JC, Shaffer C, El-Mokhtari NE, Franke A, Heilmann S, Hengstenberg C, Hoffmann P, Holmen OL, Hveem K, Jansson JH, Jöckel KH, Kessler T, Kriebel J, Laugwitz KL, Marouli E, Martinelli N, McCarthy MI, Van Zuydam NR, Meisinger C, Esko T, Mihailov E, Escher SA, Alver M, Moebus S, Morris AD, Virtamo J, Nikpay M, Olivieri O, Provost S, AlQarawi A, Robertson NR, Akinsansya KO, Reilly DF, Vogt TF, Yin W, Asselbergs FW, Kooperberg C, Jackson RD, Stahl E, Müller-Nurasyid M, Strauch K, Varga TV, Waldenberger M, Wellcome Trust Case Control Consortium, Zeng L, Chowdhury R, Salomaa V, Ford I, Jukema JW, Amouyel P, Kontto J, MORGAM Investigators, Nordestgaard BG, Ferrières J, Saleheen D, Sattar N, Surendran P, Wagner A, Young R, Howson JM, Butterworth AS, Danesh J, Ardissino D, Bottinger EP, Erbel R, Franks PW, Girelli D, Hall AS, Hovingh GK, Kastrati A, Lieb W, Meitinger T, Kraus WE, Shah SH, McPherson R, Orho-Melander M, Melander O, Metspalu A, Palmer CN, Peters A, Rader DJ, Reilly MP, Loos RJ, Reiner AP, Roden DM, Tardif JC, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Samani NJ, Schunkert H, Deloukas P, Kathiresan S, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Towards sustainable fishery management for skates in South America: The genetic population structure of Zearaja chilensis and Dipturus trachyderma (Chondrichthyes, Rajiformes) in the south-east Pacific Ocean
Feb 16, 2017   PloS One
Vargas-Caro C, Bustamante C, Bennett MB, Ovenden JR
Towards sustainable fishery management for skates in South America: The genetic population structure of Zearaja chilensis and Dipturus trachyderma (Chondrichthyes, Rajiformes) in the south-east Pacific Ocean
Feb 16, 2017
PloS One
UNASSIGNED: The longnose skates (Zearaja chilensis and Dipturus trachyderma) are the main component of the elasmobranch fisheries in the south-east Pacific Ocean. Both species are considered to be a single stock by the fishery management in Chile however, little is known about the level of demographic connectivity within the fishery. In this study, we used a genetic variation (560 bp of the control region of the mitochondrial genome and ten microsatellite loci) to explore population connectivity at five locations along the Chilean coast. Analysis of Z. chilensis populations revealed significant genetic structure among off-shore locations (San Antonio, Valdivia), two locations in the Chiloé Interior Sea (Puerto Montt and Aysén) and Punta Arenas in southern Chile. For example, mtDNA haplotype diversity was similar across off-shore locations and Punta Arenas (h = 0.46-0.50), it was significantly different to those in the Chiloé Interior Sea (h = 0.08). These results raise concerns about the long-term survival of the species within the interior sea, as population resilience will rely almost exclusively on self-recruitment. In contrast, little evidence of genetic structure was found for D. trachyderma. Our results provide evidence for three management units for Z. chilensis, and we recommend that separate management arrangements are required for each of these units. However, there is no evidence to discriminate the extant population of Dipturus trachyderma as separate management units. The lack of genetic population subdivision for D. trachyderma appears to correspond with their higher dispersal ability and more offshore habitat preference.
Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis
Feb 16, 2017   PLoS Genetics
Skwark MJ, Croucher NJ, Puranen S, Chewapreecha C, Pesonen M, Xu YY, Turner P, Harris SR, Beres SB, Musser JM, Parkhill J, Bentley SD, Aurell E, Corander J
Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis
Feb 16, 2017
PLoS Genetics
UNASSIGNED: Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein-protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly enhances the future potential of epistasis analysis for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for targeted experimental work.
Soft Selective Sweeps in Evolutionary Rescue
Feb 18, 2017   Genetics
Wilson BA, Pennings PS, Petrov DA
Soft Selective Sweeps in Evolutionary Rescue
Feb 18, 2017
Genetics
UNASSIGNED: Evolutionary rescue occurs when a population that is declining in size because of an environmental change is rescued from extinction by genetic adaptation. Evolutionary rescue is an important phenomenon at the intersection of ecology and population genetics, and the study of evolutionary rescue is critical to understanding processes ranging from species conservation to the evolution of drug and pesticide resistance. While most population genetic models of evolutionary rescue focus on estimating the probability of rescue, we focus on whether one or more adaptive lineages contribute to evolutionary rescue. We find that when evolutionary rescue is likely, it is often driven by soft selective sweeps where multiple adaptive mutations spread through the population simultaneously. We give full analytic results for the probability of evolutionary rescue and the probability that evolutionary rescue occurs via soft selective sweeps. We expect that these results will find utility in understanding the genetic signatures associated with various evolutionary rescue scenarios in large populations, such as the evolution of drug resistance in viral, bacterial, or eukaryotic pathogens. Copyright © 2017, The Genetics Society of America.
HSP90 Shapes the Consequences of Human Genetic Variation
Feb 20, 2017   Cell
Karras GI, Yi S, Sahni N, Fischer M, Xie J, Vidal M, D'Andrea AD, Whitesell L, Lindquist S
HSP90 Shapes the Consequences of Human Genetic Variation
Feb 20, 2017
Cell
UNASSIGNED: HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases. Copyright © 2017 Elsevier Inc. All rights reserved.
A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
Feb 21, 2017   Genome Medicine
Kumar D, Puan KJ, Andiappan AK, Lee B, Westerlaken GH,   . . . . . .   , Zolezzi F, Poidinger M, Lane EB, Meyaard L, Rötzschke O
A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
Feb 21, 2017
Genome Medicine
BACKGROUND: Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. METHODS: Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). RESULTS: We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10 CONCLUSION: Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.
Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types
Feb 20, 2017   Nature Genetics Add nature.com free-link Cancel
Chun S, Casparino A, Patsopoulos NA, Croteau-Chonka DC, Raby BA, De Jager PL, Sunyaev SR, Cotsapas C
Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types
Feb 20, 2017
Nature Genetics
UNASSIGNED: Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression. However, because causal variants are difficult to identify, and cis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect. Using eQTLs from three major immune subpopulations, we found shared effects in only ∼25% of the loci examined. Thus, we show that a fraction of gene-regulatory changes suggest strong mechanistic hypotheses for disease risk, but we conclude that most risk mechanisms are not likely to involve changes in basal gene expression.
Genetic mapping of yield traits using RIL population derived from Fuchuan Dahuasheng and ICG6375 of peanut (
Feb 20, 2017   Molecular Breeding : New Strategies In Plant Improvement
Chen Y, Ren X, Zheng Y, Zhou X, Huang L,   . . . . . .   , Lei Y, Liao B, Huai D, Wei W, Jiang H
Genetic mapping of yield traits using RIL population derived from Fuchuan Dahuasheng and ICG6375 of peanut (
Feb 20, 2017
Molecular Breeding : New Strategies In Plant Improvement
UNASSIGNED: The genetic architecture determinants of yield traits in peanut (
An Atypical Thioredoxin Imparts Early Resistance to Sugarcane Mosaic Virus in Maize
Feb 20, 2017   Molecular Plant
Liu Q, Liu H, Gong Y, Tao Y, Jiang L, Zuo W, Yang Q, Ye J, Lai J, Wu J, Lübberstedt T, Xu M
An Atypical Thioredoxin Imparts Early Resistance to Sugarcane Mosaic Virus in Maize
Feb 20, 2017
Molecular Plant
UNASSIGNED: Sugarcane mosaic virus (SCMV) disease causes substantial losses of grain yield and forage biomass in susceptible maize worldwide. A major quantitative trait locus, Scmv1, has been identified to impart strong resistance to SCMV at early infection stage. Here, we demonstrate that ZmTrxh, encoding an atypical h-type thioredoxin, is the causal gene at Scmv1, and that its transcript abundance correlated strongly with maize resistance to SCMV. ZmTrxh alleles, whether they are resistant or susceptible, share the identical coding/proximal promoter regions, but vary in the upstream regulatory regions. ZmTrxh lacks two canonical cysteines in the thioredoxin active-site motif and exists uniquely in maize genome. Because of this, ZmTrxh is unable to reduce disulfide bridges, but possesses a strong molecular chaperone-like activity. ZmTrxh is dispersed in maize cytoplasm to suppress SCMV viral RNA accumulation. Moreover, ZmTrxh-mediated maize resistance to SCMV showed no obvious correlation with the SA- and JA-related defense signaling pathways. Altogether, ZmTrxh exhibits a distinct defense profile in maize resistance to SCMV, differing from previously characterized dominant or recessive potyvirus resistance genes. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.
Deciphering the distance to antibiotic resistance for the pneumococcus using genome sequencing data
Feb 16, 2017   Scientific Reports
Mobegi FM, Cremers AJ, de Jonge MI, Bentley SD, van Hijum SA, Zomer A
Deciphering the distance to antibiotic resistance for the pneumococcus using genome sequencing data
Feb 16, 2017
Scientific Reports
Advances in genome sequencing technologies and genome-wide association studies (GWAS) have provided unprecedented insights into the molecular basis of microbial phenotypes and enabled the identification of the underlying genetic variants in real populations. However, utilization of genome sequencing in clinical phenotyping of bacteria is challenging due to the lack of reliable and accurate approaches. Here, we report a method for predicting microbial resistance patterns using genome sequencing data. We analyzed whole genome sequences of 1,680 Streptococcus pneumoniae isolates from four independent populations using GWAS and identified probable hotspots of genetic variation which correlate with phenotypes of resistance to essential classes of antibiotics. With the premise that accumulation of putative resistance-conferring SNPs, potentially in combination with specific resistance genes, precedes full resistance, we retrogressively surveyed the hotspot loci and quantified the number of SNPs and/or genes, which if accumulated would confer full resistance to an otherwise susceptible strain. We name this approach the 'distance to resistance'. It can be used to identify the creep towards complete antibiotics resistance in bacteria using genome sequencing. This approach serves as a basis for the development of future sequencing-based methods for predicting resistance profiles of bacterial strains in hospital microbiology and public health settings.

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