859 results found
Jun G, Ibrahim-Verbaas CA, Vronskaya M, et al., 2016, A novel Alzheimer disease locus located near the gene encoding tau protein., Molecular Psychiatry, Vol: 21, Pages: 108-117, ISSN: 1476-5578
APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also
Meyer BM, Huemer J, Rabl U, et al., 2016, Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults, Brain Structure and Function, Vol: 221, Pages: 103-114, ISSN: 1863-2661
Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.
Brossard M, Fang S, Vaysse A, et al., 2015, Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk, INTERNATIONAL JOURNAL OF CANCER, Vol: 137, Pages: 1901-1909, ISSN: 0020-7136
Bouzigon E, Nadif R, Le Moual N, et al., 2015, Genetic and environmental factors of asthma and allergy: Results of the EGEA study, REVUE DES MALADIES RESPIRATOIRES, Vol: 32, Pages: 822-840, ISSN: 0761-8425
Kiando SR, Barlassina C, Cusi D, et al., 2015, Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia, JOURNAL OF HYPERTENSION, Vol: 33, Pages: 1802-1810, ISSN: 0263-6352
Li Y, Cagirici HB, Horpaopan S, et al., 2015, Leveling the Playing Field in Homozygosity Mapping Using Map Distances, ANNALS OF HUMAN GENETICS, Vol: 79, Pages: 366-372, ISSN: 0003-4800
Kinnersley B, Kamatani Y, Labussière M, et al., 2015, Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis, European Journal of Human Genetics, Vol: 24, Pages: 717-724, ISSN: 1476-5438
To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.
Nicolas G, Wallon D, Charbonnier C, et al., 2015, Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons., European Journal of Human Genetics, Vol: 24, Pages: 710-716, ISSN: 1476-5438
Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.
Law MH, Bishop DT, Lee JE, et al., 2015, Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma, Nature Genetics, Vol: 47, Pages: 987-995, ISSN: 1546-1718
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
Lin X, Qi Q, Zheng Y, et al., 2015, Neuropeptide Y genotype, central obesity, and abdominal fat distribution: the POUNDS LOST trial, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 102, Pages: 514-519, ISSN: 0002-9165
Ojelade SA, Jia T, Rodan AR, et al., 2015, Rsu1 regulates ethanol consumption in Drosophila and humans, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: E4085-E4093, ISSN: 0027-8424
Imai A, Nakaya A, Fahiminiya S, et al., 2015, Beyond homozygosity mapping: family-control analysis based on Hamming distance for prioritizing variants in exome sequencing, Scientific Reports, Vol: 5, ISSN: 2045-2322
A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks.
Kiando S, Plouin PF, Barlassina MC, et al., 2015, EXOME SEQUENCING IN SEVEN FAMILIES AND GENE-BASED ASSOCIATION STUDIES SUPPORT GENETIC HETEROGENEITY AND SUGGEST POSSIBLE CANDIDATES FOR FIBROMUSCULAR DYSPLASIA, JOURNAL OF HYPERTENSION, Vol: 33, Pages: E79-E79, ISSN: 0263-6352
Das S, Stuart PE, Ding J, et al., 2015, Fine mapping of eight psoriasis susceptibility loci, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 23, Pages: 844-853, ISSN: 1018-4813
Allum F, Shao X, Guénard F, et al., 2015, Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants, Nature Communications, Vol: 6, ISSN: 2041-1723
Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.
Huang J, Chen J, Esparza J, et al., 2015, eQTL mapping identifies insertion- and deletion-specific eQTLs in multiple tissues, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Chen D, Gaborieau V, Zhao Y, et al., 2015, A systematic investigation of the contribution of genetic variation within the MHC region to HPV seropositivity, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 2681-2688, ISSN: 0964-6906
Liang L, Willis-Owen SA, Laprise C, et al., 2015, An epigenome-wide association study of total serum immunoglobulin E concentration, Nature, Vol: 520, Pages: 670-674, ISSN: 0028-0836
Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
Bouzigon E, Nadif R, Thompson EE, et al., 2015, A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 45, Pages: 797-806, ISSN: 0954-7894
Henrion MY, Purdue MP, Scelo G, et al., 2015, Common Variation at 1q24.1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer, PLOS One, Vol: 10, ISSN: 1932-6203
So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.
Barrett JH, Taylor JC, Bright C, et al., 2015, Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions, INTERNATIONAL JOURNAL OF CANCER, Vol: 136, Pages: 1351-1360, ISSN: 0020-7136
O'Dushlaine C, Rossin L, Lee PH, et al., 2015, Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways, NATURE NEUROSCIENCE, Vol: 18, Pages: 199-209, ISSN: 1097-6256
Desrivieres S, Lourdusamy A, Tao C, et al., 2015, Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents, MOLECULAR PSYCHIATRY, Vol: 20, Pages: 263-274, ISSN: 1359-4184
Torre S, Faucher SP, Fodil N, et al., 2015, THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis, INFECTION AND IMMUNITY, Vol: 83, Pages: 759-768, ISSN: 0019-9567
Debette S, Kamatani Y, Metso TM, et al., 2015, Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection, NATURE GENETICS, Vol: 47, Pages: 78-+, ISSN: 1061-4036
Wang Z, Zhu B, Zhang M, et al., 2014, Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 6616-6633, ISSN: 0964-6906
Gilbert R, Bonilla C, Metcalfe C, et al., 2014, Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study, Cancer Causes & Control, Vol: 26, Pages: 205-218, ISSN: 1573-7225
PURPOSE: Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer. METHODS: In a nested case-control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1-T2/T3-T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism. RESULTS: We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure. CONCLUSION: We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Chouraki V, De Bruijn RFAG, Chapuis J, et al., 2014, A genome-wide association meta-analysis of plasma A beta peptides concentrations in the elderly, MOLECULAR PSYCHIATRY, Vol: 19, Pages: 1326-1335, ISSN: 1359-4184
Kennedy JM, Fodil N, Torre S, et al., 2014, CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation, Journal of Experimental Medicine, Vol: 211, Pages: 2519-2535, ISSN: 0022-1007
We used a genome-wide screen in mutagenized mice to identify genes which inactivation protects against lethal neuroinflammation during experimental cerebral malaria (ECM). We identified an ECM-protective mutation in coiled-coil domain containing protein 88b (Ccdc88b), a poorly annotated gene that is found expressed specifically in spleen, bone marrow, lymph nodes, and thymus. The CCDC88B protein is abundantly expressed in immune cells, including both CD4+ and CD8+ T lymphocytes, and in myeloid cells, and loss of CCDC88B protein expression has pleiotropic effects on T lymphocyte functions, including impaired maturation in vivo, significantly reduced activation, reduced cell division as well as impaired cytokine production (IFN- and TNF) in response to T cell receptor engage-ment, or to nonspecific stimuli in vitro, and during the course of P. berghei infection in vivo. This identifies CCDC88B as a novel and important regulator of T cell function. The human CCDC88B gene maps to the 11q13 locus that is associated with susceptibility to several inflammatory and auto-immune disorders. Our findings strongly suggest that CCDC88B is the morbid gene underlying the pleiotropic effect of the 11q13 locus on inflammation.
Ratnapriya R, Zhan X, Fariss RN, et al., 2014, Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 5827-5837, ISSN: 0964-6906
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