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See detailDeep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
Rivas, Manuel A.; Beaudoin, Melissa; Gardet, Agnes et al

in Nature Genetics (2012), 43(11), 1066-73

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants ... [more ▼]

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximately 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. [less ▲]

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See detailGenome-wide association analysis identifies susceptibility loci for migraine without aura.
Freilinger, Tobias; Anttila, Verneri; de Vries, Boukje et al

in Nature Genetics (2012), 44(7), 777-82

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this ... [more ▼]

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 x 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 x 10(-4); combined P = 7.06 x 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 x 10(-4); combined P = 1.17 x 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 x 10(-8) and P = 0.02; combined P = 3.86 x 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder. [less ▲]

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See detailThe long and winding road from correlation to causation.
Georges, Michel ULg

in Nature Genetics (2011), 43(3), 180-1

Follow-up studies of a Crohn's disease risk locus encompassing IRGM have revealed unexpected complexity. A new study shows that a synonymous variant in the IRGM coding region alters a binding site for miR ... [more ▼]

Follow-up studies of a Crohn's disease risk locus encompassing IRGM have revealed unexpected complexity. A new study shows that a synonymous variant in the IRGM coding region alters a binding site for miR-196 and modulates IRGM-dependent autophagy, adding to the list of possible mechanisms by which this locus influences disease risk. [less ▲]

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See detailMeta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W et al

in Nature Genetics (2011), 43(3), 246-52

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association ... [more ▼]

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. [less ▲]

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See detailVariants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature.
Karim, Latifa ULg; Takeda, Haruko ULg; Lin, Li et al

in Nature Genetics (2011), 43(5), 405-13

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a approximately 780-kb interval using a Hidden Markov Model-based approach that simultaneously exploits ... [more ▼]

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a approximately 780-kb interval using a Hidden Markov Model-based approach that simultaneously exploits linkage and linkage disequilibrium. We re-sequenced the interval in six sires with known QTL genotype and identified 13 clustered candidate quantitative trait nucleotides (QTNs) out of >9,572 discovered variants. We eliminated five candidate QTNs by studying the phenotypic effect of a recombinant haplotype identified in a breed diversity panel. We show that the QTL influences fetal expression of seven of the nine genes mapping to the approximately 780-kb interval. We further show that two of the eight candidate QTNs, mapping to the PLAG1-CHCHD7 intergenic region, influence bidirectional promoter strength and affect binding of nuclear factors. By performing expression QTL analyses, we identified a splice site variant in CHCHD7 and exploited this naturally occurring null allele to exclude CHCHD7 as single causative gene. [less ▲]

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See detailCCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs.
Merveille, Anne-Christine ULg; Davis, Erica E; Becker-Heck, Anita et al

in Nature Genetics (2011), 43(1), 72-8

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of ... [more ▼]

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex. [less ▲]

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See detailResequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Momozawa, Yukihide ULg; Mni, Myriam ULg; Nakamura, Kayo ULg et al

in Nature Genetics (2011), 43(1), 43-7

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20 ... [more ▼]

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. [less ▲]

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See detailMutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Endele, Sabine; Rosenberger, Georg; Geider, Kirsten et al

in Nature Genetics (2010), 42(11), 1021-6

N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca(2 ... [more ▼]

N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca(2)(+)-permeable cation channels which are blocked by extracellular Mg(2)(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg(2)(+) block and a decrease in Ca(2)(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected. [less ▲]

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See detailGenome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C et al

in Nature Genetics (2010), 42(12), 1118-25

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in ... [more ▼]

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. [less ▲]

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See detailGenome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
Anttila, Verneri; Stefansson, Hreinn; Kallela, Mikko et al

in Nature Genetics (2010), 42(10), 869-73

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular ... [more ▼]

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10, permuted threshold for genome-wide significance 7.7 x 10. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine. [less ▲]

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See detailGenome-wide association study identifies sequence variants within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
Gretarsdottir, Solveig; Baas, Annette F.; Thorleifsson, G. et al

in Nature Genetics (2010)

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See detailMutations in PYCR1 cause cutis laxa with progeroid features.
Reversade, Bruno; Escande-Beillard, Nathalie; Dimopoulou, Aikaterini et al

in Nature Genetics (2009), 41(9), 1016-21

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity ... [more ▼]

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues. [less ▲]

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See detailCommon variants at five new loci associated with early-onset inflammatory bowel disease.
Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne et al

in Nature Genetics (2009), 41(12), 1335-40

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide ... [more ▼]

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD. [less ▲]

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See detailMutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies
Bielas, S. L.; Silhavy, J. L.; Brancati, F. et al

in Nature Genetics (2009), 41

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1 ... [more ▼]

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation (‘molar tooth sign’), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly2 and is included in the newly emerging group of ‘ciliopathies’. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function [less ▲]

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See detailCommon variants in the NLRP3 region contribute to Crohn's disease susceptibility.
Villani, Alexandra-Chloé; Lemire, Mathieu; Fortin, Geneviève et al

in Nature Genetics (2009), 41(1), 71-6

We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with ... [more ▼]

We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease. [less ▲]

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See detailINPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse
Jacoby, Monique; Cox, James J.; Gayral, Stéphanie et al

in Nature Genetics (2009), 41

The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing1–3. Here, we report that mice ... [more ▼]

The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing1–3. Here, we report that mice deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor a (PDGFRa) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction. [less ▲]

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See detailDeficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism.
Aragones, Julian; Schneider, Martin; Van Geyte, Katie et al

in Nature Genetics (2008), 40

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen ... [more ▼]

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. [less ▲]

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See detailHighly effective SNP-based association mapping and management of recessive defects in livestock.
Charlier, Carole ULg; Coppieters, Wouter ULg; Rollin, Frédéric ULg et al

in Nature Genetics (2008), 40(4), 449-54

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal ... [more ▼]

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings. [less ▲]

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See detailGenome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
Barrett, Jeffrey C.; Hansoul, Sarah ULg; Nicolae, Dan L. et al

in Nature Genetics (2008), 40(8), 955-62

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total ... [more ▼]

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development. [less ▲]

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See detailThe same sequent variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.
Helgadottir, Anne; Thorleifsson, Gudmar; Magnusson, Kristinn et al

in Nature Genetics (2008), 40

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