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Ligthart L.,VU University Amsterdam | Ligthart L.,EMGO Institute for Health and Care Research EMGO | De Vries B.,Leiden University | Smith A.V.,Heart Preventive Clinic and Research Institute | And 29 more authors.
European Journal of Human Genetics | Year: 2011

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10 980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value10 5. The best result was obtained for SNP rs9908234, which had a P-value of 8.00 × 10 8. This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate. © 2011 Macmillan Publishers Limited All rights reserved. Source


Yang J.,Queensland Institute of Medical Research | Weedon M.N.,University of Exeter | Purcell S.,Cambridge Broad Institute | Purcell S.,Massachusetts General Hospital | And 19 more authors.
European Journal of Human Genetics | Year: 2011

Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and genomic control can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ∼4000 and ∼133 000 individuals. © 2011 Macmillan Publishers Limited All rights reserved. Source


Pfeufer A.,TU Munich | Pfeufer A.,Helmholtz Center for Environmental Research | Van Noord C.,Erasmus Medical Center | Marciante K.D.,University of Washington | And 77 more authors.
Nature Genetics | Year: 2010

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation. Source


Kilpelainen T.O.,Institute of Metabolic Science | Zillikens M.C.,Erasmus University Rotterdam | Stancakova A.,Kuopio University Hospital | Finucane F.M.,Institute of Metabolic Science | And 139 more authors.
Nature Genetics | Year: 2011

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10-6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10-26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10-11) and one near SPRY2 (P = 3 × 10-8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. © 2011 Nature America, Inc. All rights reserved. Source


Glessner J.T.,Childrens Hospital of Philadelphia | Smith A.V.,Heart Preventive Clinic and Research Institute | Smith A.V.,University of Iceland | Panossian S.,Childrens Hospital of Philadelphia | And 17 more authors.
PLoS ONE | Year: 2013

Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P = 3.33×10-8-1.6×10-2 unadjusted), while only one duplication was enriched in the geriatric cohort (P = 6.3×10-4). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P = 5.16×10-5-4.26×10-2) in the replication cohort. Three deletions and four duplications were significant combined (combined P = 3.7×10-4-3.9×10-2). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing (P = 0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan. © 2013 Glessner et al. Source

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