Showing papers by "Thorgeir E. Thorgeirsson published in 2017"
TL;DR: It is found that CH is very common in the elderly, trending toward inevitability, and somatic mutations in TET2, DNMT3A, ASXL1, and PPM1D are associated with CH at high significance, however, known CD mutations were evident in only a fraction of CH cases.
549 citations
International Agency for Research on Cancer1, Lunenfeld-Tanenbaum Research Institute2, Dartmouth College3, Harvard University4, National Institutes of Health5, University of Cambridge6, University of Copenhagen7, Copenhagen University Hospital8, Gentofte Hospital9, University of Texas MD Anderson Cancer Center10, University of Hawaii11, University of Göttingen12, Vanderbilt University Medical Center13, Case Western Reserve University14, University of Oviedo15, Technion – Israel Institute of Technology16, University of Sheffield17, University of Liverpool18, Radboud University Nijmegen19, Washington State University Spokane20, National Institute of Occupational Health21, BC Cancer Agency22, Nanjing Medical University23, New Generation University College24, University of Pittsburgh25, University of Milan26, Princess Margaret Cancer Centre27, University of Southern California28, Sejong University29, Lund University30, Imperial College London31, Aarhus University32, Prevention Institute33, Fred Hutchinson Cancer Research Center34, Ludwig Maximilian University of Munich35, Technische Universität München36, University Hospital Heidelberg37, Umeå University38, University of Kentucky39, Charles University in Prague40, University of Ostrava41, University of Belgrade42, Nofer Institute of Occupational Medicine43, University of Bergen44, National University of Singapore45, Institute of Cancer Research46, American Cancer Society47, Merck & Co.48, University of British Columbia49, University Medical Center Groningen50, University of Leicester51, National Institute for Health Research52, Amgen53, Research Triangle Park54, Washington University in St. Louis55, Baylor College of Medicine56, Anschutz Medical Campus57, University of Washington58, Centre for Addiction and Mental Health59, University of Toronto60, QIMR Berghofer Medical Research Institute61, Laval University62
TL;DR: 18 susceptibility loci achieving genome-wide significance are identified, including 10 new loci linked with lung cancer overall and six loci associated with lung adenocarcinoma, highlighting the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer.
Abstract: Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
405 citations
TL;DR: High genetic correlations were found between extraversion and attention-deficit–hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder, and between neuroticism and openness to experience were clustered with the disorders.
Abstract: Personality is influenced by genetic and environmental factors and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit-hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).
337 citations
King's College London1, Cardiff University2, Aarhus University3, University of Adelaide4, Virginia Commonwealth University5, University of Edinburgh6, University Hospital of Lausanne7, University of Queensland8, University of New England (Australia)9, Harvard University10, Massachusetts Institute of Technology11, Charité12, deCODE genetics13, Greifswald University Hospital14, Karolinska Institutet15, University of Münster16, VU University Amsterdam17, University of Lausanne18, University of Marburg19, University of Bonn20, QIMR Berghofer Medical Research Institute21, University of California, San Francisco22, Washington University in St. Louis23, University of Aberdeen24, University of Greifswald25, Max Planck Society26, University of Copenhagen27, University of Gothenburg28, Heidelberg University29, Stanford University30, VU University Medical Center31, Aarhus University Hospital32, University of Liverpool33, Queensland University of Technology34, University of Glasgow35, Florida Atlantic University36, Roy J. and Lucille A. Carver College of Medicine37, University of Granada38, National Institutes of Health39, Group Health Cooperative40, University of Iceland41, University of Dundee42, University of North Carolina at Chapel Hill43, Columbia University44
TL;DR: It is demonstrated that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size.
150 citations
TL;DR: An Icelandic kindred containing ten individuals with psychosis is investigated, finding that all affected individuals carry RBM12, a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif, and carriers unaffected by psychosis resemble patients with schizophrenia.
Abstract: Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia.
70 citations
TL;DR: In the combined Icelandic and Danish data sets, significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15) and FAM155A (family with sequence similarity 155A) are observed, the first loci shown to associate with diverticular disease in a genome-wide study.
Abstract: Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10−18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10−10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10−11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study. A hallmark of diverticular disease is pouches in the bowel wall which can become infected and inflamed, causing the more severe diverticulitis. Here, the authors report the first genome-wide association study on these interconnected conditions and identifyARHGAP15, COLQ and FAM155Aas novel risk loci.
60 citations
Journal Article•
47 citations
TL;DR: A genome-wide association study on herniated lumbar disc herniation cases and population controls is performed and it is speculated that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH.
Abstract: Lumbar disc herniation (LDH) is common and often debilitating. Microdiscectomy of herniated lumbar discs (LDHsurg) is performed on the most severe cases to resolve the resulting sciatica. Here we perform a genome-wide association study on 4,748 LDHsurg cases and 282,590 population controls and discover 37 highly correlated markers associating with LDHsurg at 8q24.21 (between CCDC26 and GSDMC), represented by rs6651255[C] (OR=0.81; P=5.6 × 10-12) with a stronger effect among younger patients than older. As rs6651255[C] also associates with height, we performed a Mendelian randomization analysis using height polygenic risk scores as instruments to estimate the effect of height on LDHsurg risk, and found that the marker's association with LDHsurg is much greater than predicted by its effect on height. In light of presented findings, we speculate that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH.
37 citations
TL;DR: The results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within the results.
Abstract: Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to impute genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder. We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB). We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.
21 citations
TL;DR: A potential therapeutic use in CUD of compounds with agonistic effect on the neuronal acetylcholine receptor alpha-2 subunit encoded by CHRNA2 is indicated, with a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.
Abstract: Cannabis is among the most frequently used illicit psychoactive substance worldwide. Life time use was reported among 35 to 40% of adults in Denmark and the United States. Cannabis use is increasing in the population and among users around 9% become dependent. The genetic risk component is high with heritability estimates of 51 to 70%. Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, P=9.31x10-12) that replicates in an independent population (Preplication=3.27x10-3, Pmetaanalysis=9.09x10-12) based on genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD, indicating potential therapeutic use in CUD of compounds with agonistic effect on CHRNA2. At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.
20 citations
TL;DR: It is shown that non-transmitted alleles can impact a child through their effects on the parents and other relatives, a phenomenon the authors call genetic nurture, and the genetic nurturing effects of this polygenic score extend to other traits.
Abstract: Sequence variants in the parental genomes that are not transmitted to a child/proband are often ignored in genetic studies. Here we show that non-transmitted alleles can impact a child through their effects on the parents and other relatives, a phenomenon we call genetic nurture. Using results from a meta-analysis of educational attainment, the polygenic score computed for the non-transmitted alleles of 21,637 probands with at least one parent genotyped has an estimated effect on the educational attainment of the proband that is 29.9% (P = 1.6×10 -14 ) of that of the transmitted polygenic score. Genetic nurturing effects of this polygenic score extend to other traits. Paternal and maternal polygenic scores have similar effects on educational attainment, but mothers contribute more than fathers to nutrition/heath related traits.