Takahashi M.,Kyoto University |
Saenko V.A.,Nagasaki University |
Rogounovitch T.I.,Nagasaki University |
Kawaguchi T.,Kyoto University |
And 11 more authors.
Human Molecular Genetics | Year: 2010
Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 × 10-9 to 4.9 × 10-9). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 × 10-12, OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC. © The Author 2010. Published by Oxford University Press. All rights reserved.
Priebe L.,University of Bonn |
Degenhardt F.A.,University of Bonn |
Herms S.,University of Bonn |
Haenisch B.,University of Bonn |
And 21 more authors.
Molecular Psychiatry | Year: 2012
We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset ≤21 years (AO≤21years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO≤21years and AO>21years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO≤21years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO≤21years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO≤21years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD. © 2012 Macmillan Publishers Limited All rights reserved.
PubMed | Institute Genomique, Karolinska Institutet, University of Cagliari, Fondation Jean Dausset CEPH and 75 more.
Type: Journal Article | Journal: PloS one | Year: 2014
Alzheimers disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimers Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimers cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p=1.410-6) and 14 (IGHV1-67 p=7.910-8) which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimers disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
PubMed | Institute Genomique, University of Nottingham, University of California at Los Angeles, Medical University of Graz and 44 more.
Type: Journal Article | Journal: Molecular psychiatry | Year: 2015
APOE 4, 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 Alzheimers Project (IGAP) Consortium in APOE 4+ (10352 cases and 9207 controls) and APOE 4- (7184 cases and 26968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE 4 status. Suggestive associations (P<1 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE 4+: 1250 cases and 536 controls; APOE 4-: 718 cases and 1699 controls). Among APOE 4- 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=58 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 4+ subjects (CR1 and CLU) or APOE 4- 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=16 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 (P1.2 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 10(-6)) and temporal cortex (P=2.6 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE 4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
PubMed | Institute Genomique, University of Washington, Lille University Hospital Center, Erasmus Medical Center and 5 more.
Type: Journal Article | Journal: Molecular psychiatry | Year: 2014
Amyloid beta (A) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, A peptides functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma A peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant A-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3528 healthy individuals of European descent and for whom plasma A1-40 and A1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma A1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate A1-42 secretion. In conclusion, our study results suggest that plasma A peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
Furney S.J.,King's College London |
Simmons A.,King's College London |
Breen G.,King's College London |
Pedroso I.,King's College London |
And 17 more authors.
Molecular Psychiatry | Year: 2011
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the ZNF292 gene (rs1925690; P-value=2.6 × 10 -8; corrected P-value for equivalent number of independent quantitative traits=7.7 × 10 -8) and an intergenic SNP, flanking the ARPP-21 gene, with an overall effect on entorhinal cortical thickness (rs11129640; P-value=5.6 × 10 -8; corrected P-value=1.7 × 10 -7). Gene-wide scoring also highlighted PICALM as the most significant gene associated with entorhinal cortical thickness (P-value=6.7 × 10 -6). © 2011 Macmillan Publishers Limited All rights reserved.
PubMed | U.S. National Institute on Aging, University of Michigan, Memorial University of Newfoundland, Imperial College London and 3 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2015
Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 10(-74)), rs6924962 (P = 3.21 10(-19)) and rs892666 (P = 1.11 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 10(-16)) and rs918518 (P = 3.22 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 10(-13)), IL13 (rs1295685; P = 1.65 10(-7)), IL23A (rs61937678; P = 1.82 10(-7)) and TNFAIP3 (rs642627; P = 5.90 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.