Featured
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| Open AccessAutosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation
DNA methylation is critically involved in X chromosome inactivation (XCI) and dosage compensation, yet some X-chromosomal genes escape XCI. Here, Lujik et al. identify three autosomal genetic loci that associate with differential DNA methylation near genes that variably escape XCI in females.
- René Luijk
- , Haoyu Wu
- & Bastiaan T. Heijmans
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Article
| Open AccessIdentification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Multiple myeloma is a cancer of the plasma cells, and the complete aetiology of the disease is still unclear. Here the authors perform an additional GWAS analysis followed by a meta-analysis with existing GWAS and replication genotyping and identify 6 novel risk loci and utilise gene expression, epigenetic profiling and in situ Hi-C data to further our understanding of MM susceptibility.
- Molly Went
- , Amit Sud
- & Stephen N. Thibodeau
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Article
| Open AccessExome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations
Pancreatic ductal adenocarcinoma is a lethal human cancer with a poor 5-year overall survival rate. Here the authors perform an exome-wide analysis in a cohort of PDAC patients to identify three novel missense variants in PKN1, DOK2, and APOB genes, that are associated with PDAC risk.
- Jiang Chang
- , Jianbo Tian
- & Xiaoping Miao
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Article
| Open AccessGWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation
IL-1β in gingival crevicular fluid (GCF) is a marker of inflammation in periodontal disease. Here, Offenbacher et al. identify genetic variants in the IL37 locus associated with GCF-IL-1β and show that the IL-1β-increasing allele at rs3811046 leads to an enhanced inflammatory response in vitro and in vivo.
- Steven Offenbacher
- , Yizu Jiao
- & Kari E. North
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Article
| Open AccessVariants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits
Uterine leiomyomas are common benign tumors. Here, a meta-analysis of two European leiomyoma GWAS uncovers 21 leiomyoma risk variants at 16 loci, providing evidence of genetic overlap between leiomyoma and various benign and malignant tumors and highlighting the role of estrogen in tumor growth.
- Thorunn Rafnar
- , Bjarni Gunnarsson
- & Kari Stefansson
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Article
| Open AccessFast and powerful genome wide association of dense genetic data with high dimensional imaging phenotypes
Genome-wide association studies (GWAS) of neuroimaging data pose a significant computational burden because of the need to correct for multiple testing in both the genetic and the imaging data. Here, Ganjgahi et al. develop WLS-REML which significantly reduces computation running times in brain imaging GWAS.
- Habib Ganjgahi
- , Anderson M. Winkler
- & Thomas E. Nichols
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Article
| Open AccessGenome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility
Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.
- Mitchell J. Machiela
- , Thomas G. P. Grünewald
- & Olivier Delattre
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Article
| Open AccessIdentification of nine new susceptibility loci for endometrial cancer
Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
- Tracy A. O’Mara
- , Dylan M. Glubb
- & Deborah J. Thompson
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Article
| Open AccessGenome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia
Educational attainment and schizophrenia have a negative phenotypic relationship but show positive genetic correlation. Here, the authors study genetic dependence between the two traits and find that multiple genes have pleiotropic effects on both without a systematic pattern of sign concordance.
- V. Bansal
- , M. Mitjans
- & P. D. Koellinger
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Article
| Open AccessAND-1 fork protection function prevents fork resection and is essential for proliferation
AND-1, the vertebrate orthologue of Ctf4, is a critical player during DNA replication and for maintenance of genome integrity. Here the authors use a conditional AND-1 depletion system in avian DT40 cells to reveal the consequences of the lack of AND-1 on cell proliferation and DNA replication.
- Takuya Abe
- , Ryotaro Kawasumi
- & Dana Branzei
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Article
| Open AccessMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function
Pulmonary function is influenced by environmental factors, lifestyle, and genetics. Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry.
- Annah B. Wyss
- , Tamar Sofer
- & Stephanie J. London
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Article
| Open AccessGenome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
- Angli Xue
- , Yang Wu
- & Jian Yang
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Article
| Open AccessPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
- Jessica van Setten
- , Jennifer A. Brody
- & Nona Sotoodehnia
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Article
| Open AccessDeep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries
Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.
- Seyedeh M. Zekavat
- , Sanni Ruotsalainen
- & Sebastian Zoellner
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Article
| Open AccessElucidating the genetic basis of social interaction and isolation
Little is known about the genetic determinants of social isolation and loneliness despite their well-established importance for health. Here, using multi-trait GWAS, Day et al. identify 15 genomic loci for loneliness and further show a bidirectional causal relationship between BMI and loneliness by MR.
- Felix R. Day
- , Ken K. Ong
- & John R. B. Perry
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Correspondence
| Open AccessReply to ‘Misestimation of heritability and prediction accuracy of male-pattern baldness’
- Nicola Pirastu
- , Peter K. Joshi
- & James F. Wilson
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Article
| Open AccessIBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.
- Yukihide Momozawa
- , Julia Dmitrieva
- & Michel Georges
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Article
| Open AccessGenetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
- Viktoria Gusarova
- , Colm O’Dushlaine
- & Jesper Gromada
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Article
| Open AccessIdentifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
To comprehend the genetic regulatory mechanisms underlying brain-related traits in humans, Qi et al. estimate the correlation of expression and DNA methylation QTL effects in cis between blood and brain and show that using blood eQTL/mQTL data of large sample size can increase power in gene discovery for brain-related traits and diseases.
- Ting Qi
- , Yang Wu
- & Jian Yang
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Article
| Open AccessA multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci
Primary open-angle glaucoma (POAG) leads to progressive vision loss. Here, Choquet et al. perform genome-wide association analysis for POAG in a multi-ethnic cohort, identify a total of nine novel genetic loci and show relevant function of FMNL2 and LMX1B using cell line and mouse experiments.
- Hélène Choquet
- , Seyyedhassan Paylakhi
- & Eric Jorgenson
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Article
| Open AccessStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.
- Gail Davies
- , Max Lam
- & Ian J. Deary
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Article
| Open AccessElucidating the genetic architecture of reproductive ageing in the Japanese population
The timing of female reproductive capacity is influenced by genetic and environmental factors. Here, in genome-wide association studies, the authors identify genetic loci for age at menarche and onset of menopause in Japanese women, and highlight differences with European populations.
- Momoko Horikoshi
- , Felix R. Day
- & John. R. B. Perry
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Article
| Open AccessThirty loci identified for heart rate response to exercise and recovery implicate autonomic nervous system
Genome-wide association studies have identified multiple loci for resting heart rate (HR) but the genetic factors associated with HR increase during and HR recovery after exercise are less well studied. Here, the authors examine both traits in a two-stage GWAS design in up to 67,257 individuals from UK Biobank.
- Julia Ramírez
- , Stefan van Duijvenboden
- & Patricia B. Munroe
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Article
| Open AccessA joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications
In GWAS, waist-to-hip ratio (WHR) is often adjusted for body mass index (BMI) to account for their correlation (WHRadjBMI). Here, Winkler et al. classify 159 genetic variants for BMI, WHR, or WHRadjBMI based on their effect directions for BMI and WHR to differentiate subtypes of adiposity genetics.
- Thomas W Winkler
- , Felix Günther
- & Iris M Heid
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Article
| Open AccessA whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.
- Karol Estrada
- , Christopher W. Whelan
- & Daniel G. MacArthur
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Article
| Open AccessCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
- Adriana I. Iglesias
- , Aniket Mishra
- & Stuart MacGregor
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Article
| Open AccessGlobal genetic differentiation of complex traits shaped by natural selection in humans
Human complex traits and disorders often show differentiation among populations. Here, the authors analyze SNPs associated with 10 complex traits using data of large sample size from African, East Asian and European populations, and find significant genetic differentiation among global populations shaped by natural selection.
- Jing Guo
- , Yang Wu
- & Jian Yang
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Article
| Open AccessExploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.
- Alvaro N. Barbeira
- , Scott P. Dickinson
- & Hae Kyung Im
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Article
| Open AccessGenome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure
The skin’s tanning response to sun exposure shows great interindividual variability. Here, Visconti et al. perform a genome-wide association study for ease of skin tanning and identify 20 genetic loci, ten of which had not previously been associated with pigmentation-related traits.
- Alessia Visconti
- , David L. Duffy
- & Mario Falchi
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Article
| Open AccessCCDC102B confers risk of low vision and blindness in high myopia
Myopic maculopathy is a complication of myopia that often progresses to blindness. Here, in a genome-wide association study, Hosoda et al. find that rs11873439 intronic to CCDC102B is associated with myopic maculopathy, but not with myopia, thus representing a risk factor independent of myopia.
- Yoshikatsu Hosoda
- , Munemitsu Yoshikawa
- & Kenji Yamashiro
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Article
| Open AccessAncient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans
Leprosy, caused by infection with Mycobacterium leprae, was common in Europe in the Middle Ages. Here, Krause-Kyora et al. analyze ancient DNA from a medieval Danish leprosarium to assemble 10 complete bacterial genomes and perform association analysis of the DRB1*15:01 allele with risk of leprosy infection.
- Ben Krause-Kyora
- , Marcel Nutsua
- & Almut Nebel
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Article
| Open AccessThe genetic architecture of floral traits in the woody plant Prunus mume
Mei (Prunus mume) is a woody tree that produces ornamental blossoms which symbolize spring in East Asia. Here, Zhang et al. resequence wild and domesticated mei to reveal considerable admixture and introgression from other Prunus species and identify loci associated with floral traits.
- Qixiang Zhang
- , He Zhang
- & Tangren Cheng
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Article
| Open AccessAnalysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
- Connor A. Emdin
- , Amit V. Khera
- & Sekar Kathiresan
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Article
| Open AccessMedical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.
- Christopher DeBoever
- , Yosuke Tanigawa
- & Manuel A. Rivas
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Article
| Open AccessGenome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways
The UK Biobank provides data for three depression-related phenotypes. Here, Howard et al. perform a genome-association study for broad depression, probable major depressive disorder (MDD) and hospital record-coded MDD in up to 322,580 UK Biobank participants which highlights excitatory synaptic pathways.
- David M. Howard
- , Mark J. Adams
- & Andrew M. McIntosh
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Article
| Open AccessGenome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
While GWAS have uncovered susceptibility loci for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), much of the heritable risk remains undiscovered. Here, the authors perform a meta-analysis of two existing BCP-ALL GWAS together with an unpublished GWAS to identify risk loci at 8q24.21 and 2q22.3.
- Jayaram Vijayakrishnan
- , James Studd
- & Richard S. Houlston
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Article
| Open AccessPlacenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum
Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting associated with unfavourable outcomes during pregnancy. Here, Fejzo et al. perform genome-wide scans for HG and pregnancy nausea and vomiting and identify genetic associations at two loci implicating the genes GDF15 and IGFBP7.
- Marlena S. Fejzo
- , Olga V. Sazonova
- & Catherine H. Wilson
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Article
| Open AccessRisk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4
Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in children and HIV-infected adults in Africa. Here, Gilchrist et al. conduct a genome-wide association study and show that genetic variation in STAT4 is a determinant of NTS in Kenyan and Malawian children.
- James J. Gilchrist
- , Anna Rautanen
- & Adrian V. S. Hill
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Article
| Open AccessGenome-wide analysis yields new loci associating with aortic valve stenosis
Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.
- Anna Helgadottir
- , Gudmar Thorleifsson
- & Kari Stefansson
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Article
| Open AccessImproving genetic prediction by leveraging genetic correlations among human diseases and traits
Genetic prediction of complex traits so far has limited accuracy because of insufficient understanding of the genetic risk. Here, Maier et al. develop an improved method for trait prediction that makes use of genetic correlations between traits and apply it to summary statistics of psychiatric diseases.
- Robert M. Maier
- , Zhihong Zhu
- & Matthew R. Robinson
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Article
| Open AccessA transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis
Progressive remodeling and calcification of the aortic valve leads to calcific aortic valve stenosis (CAVS) and, ultimately, heart failure. In a combined GWAS and TWAS approach, Thériault et al. identify PALMD as a candidate causal gene for CAVS, which is further supported by Mendelian randomization.
- Sébastien Thériault
- , Nathalie Gaudreault
- & Yohan Bossé
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Article
| Open AccessItem-level analyses reveal genetic heterogeneity in neuroticism
Neuroticism can be assessed as a composite score of individual items. Here, Nagel et al. perform genetic association studies for 12 neuroticism items and the sum-score and demonstrate genetic heterogeneity at the item-level.
- Mats Nagel
- , Kyoko Watanabe
- & Sophie van der Sluis
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Article
| Open AccessGenetic study links components of the autonomous nervous system to heart-rate profile during exercise
Response of the heart rate (HR) to exercise is associated with cardiac fitness and risk of cardiac death. Here, in a genome-wide association study, Verweij et al. identify 23 loci for HR increase during exercise or HR recovery, and highlight pleiotropy with blood pressure by polygenic risk score analysis.
- Niek Verweij
- , Yordi J. van de Vegte
- & Pim van der Harst
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Article
| Open AccessComprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes
More than 100 risk loci for schizophrenia have been identified by genome-wide association studies. Here, the authors apply an integrative genomic approach to prioritize risk genes and validate GLT8D1 and CSNK2B as candidate causal genes by in vitro studies in neural stem cells.
- Cui-Ping Yang
- , Xiaoyan Li
- & Xiong-Jian Luo
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Article
| Open AccessTranscriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly
Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer.
- Peer Aramillo Irizar
- , Sascha Schäuble
- & Christoph Kaleta
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Article
| Open AccessGWAS of epigenetic aging rates in blood reveals a critical role for TERT
Epigenetic clocks based on DNA methylation levels are estimators of chronological age. Here, the authors perform a GWAS of epigenetic aging rates in blood and find SNP variants in the TERT locus associated with increased intrinsic epigenetic age are also associated with longer telomeres.
- Ake T. Lu
- , Luting Xue
- & Steve Horvath
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Article
| Open AccessWhole-exome sequencing identifies common and rare variant metabolic QTLs in a Middle Eastern population
Blood metabolites are influenced by a combination of genetic and environmental factors. Here, Yousri and colleagues perform a whole-exome sequencing study in combination with a metabolomics analysis to identify metabolic quantitative trait loci in a Middle Eastern population.
- Noha A. Yousri
- , Khalid A. Fakhro
- & Karsten Suhre
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Article
| Open AccessRe-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.
- Sílvia Bonàs-Guarch
- , Marta Guindo-Martínez
- & David Torrents
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Article
| Open AccessGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.
- Xia Jiang
- , Paul F. O’Reilly
- & Douglas P. Kiel