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      Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium ( N=53 949)

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      Molecular Psychiatry
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          Abstract

          General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10 −9, MIR2113; rs17522122, P=2.55 × 10 −8, AKAP6; rs10119, P=5.67 × 10 −9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P=1 × 10 −6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N=6617) and the Health and Retirement Study ( N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N=5487; P=1.5 × 10 −17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

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          Most cited references46

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          Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

          Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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            Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

            The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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              • Abstract: found
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              Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.

              Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                February 2015
                03 February 2015
                : 20
                : 2
                : 183-192
                Affiliations
                [1 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh , Edinburgh, UK
                [2 ]Department of Psychology, University of Edinburgh , Edinburgh, UK
                [3 ]School of Mathematics and Statistics, University of Sydney , Sydney, NSW, Australia
                [4 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , Seattle, WA, USA
                [5 ]Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston , Houston, TX, USA
                [6 ]Inserm-UMR744, Institut Pasteur de Lille, Unité d'Epidémiologie et de Santé Publique , Lille, France
                [7 ]Department of Neurology, Boston University School of Medicine , Boston, MA, USA
                [8 ]K.G. Jebsen Centre for Psychosis Research and the Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen , Bergen, Norway
                [9 ]Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital , Bergen, Norway
                [10 ]Department of Neurology, Medical University of Graz , Graz, Austria
                [11 ]Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz , Graz, Austria
                [12 ]Department of Neurology, Erasmus University Medical Center , Rotterdam, The Netherlands
                [13 ]Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center , Rotterdam, The Netherlands
                [14 ]Centre for Population Health Sciences, University of Edinburgh , Edinburgh, UK
                [15 ]Institute of Behavioural Sciences, University of Helsinki , Helsinki, Finland
                [16 ]Folkhälsan Research Centre , Helsinki, Finland
                [17 ]Max Planck Institute for Human Development , Berlin, Germany
                [18 ]Max Planck Institute for Molecular Genetics , Berlin, Germany
                [19 ]Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital , Edinburgh, UK
                [20 ]Queensland Brain Institute, The University of Queensland , Brisbane, QLD, Australia
                [21 ]Hunter Medical Research Institute and Faculty of Health, University of Newcastle , Newcastle, NSW, Australia
                [22 ]Department of Gerontology and Geriatrics, Leiden University Medical Center , Leiden, The Netherlands
                [23 ]Netherlands Consortium for Healthy Ageing , Leiden, The Netherlands
                [24 ]Icelandic Heart Association , Kopavogur, Iceland
                [25 ]University of Iceland , Reykjavik, Iceland
                [26 ]Department of Epidemiology, University of Michigan , Ann Arbor, MI, USA
                [27 ]Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales , Sydney, NSW, Australia
                [28 ]Menzies Research Institute , Hobart, Tasmania
                [29 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh , Edinburgh, UK
                [30 ]Framingham Heart Study , Framingham, MA, USA
                [31 ]Department of Biostatistics, Boston University School of Public Health , Boston, MA, USA
                [32 ]Rush Alzheimer's Disease Center, Rush University Medical Center , Chicago, IL, USA
                [33 ]Department of Public Health and Primary Care, Trinity College Dublin , Dublin, Ireland
                [34 ]Andrija Stampar School of Public Health, Medical School, University of Zagreb , Zagreb, Croatia
                [35 ]Department of Epidemiology, Erasmus University Medical Center , Rotterdam, The Netherlands
                [36 ]Netherlands Consortium for Healthy Ageing , Leiden, The Netherlands
                [37 ]National Ageing Research Institute, Royal Melbourne Hospital , Melbourne, VIC, Australia
                [38 ]Academic Unit for Psychiatry of Old Age, St George's Hospital, University of Melbourne , Kew, Australia
                [39 ]Department of Neurology, University of Pittsburgh , Pittsburgh, PA, USA
                [40 ]Department of Psychiatry, University of Pittsburgh , Pittsburgh, PA, USA
                [41 ]Department of Psychology, University of Pittsburgh , Pittsburgh, PA, USA
                [42 ]Inserm, U106 , Montpellier, France
                [43 ]Université Montpellier I , Montpellier, France
                [44 ]Faculty of Medicine, School of Public Health, Imperial College , London, UK
                [45 ]Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston , Houston, TX, USA
                [46 ]Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX, USA
                [47 ]Department of Pharmacology and Therapeutics, University College Cork , Cork, Ireland
                [48 ]Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital , Boston, MA, USA
                [49 ]Harvard Medical School , Boston, MA, USA
                [50 ]Program in Medical and Population Genetics, Broad Institute , Cambridge, MA, USA
                [51 ]Inserm U708, Neuroepidemiology , Paris, France
                [52 ]Inserm U897, Université Bordeaux Segalen , Bordeaux, France
                [53 ]National Institute for Health and Welfare , Helsinki, Finland
                [54 ]Department of General Practice and Primary health Care, University of Helsinki , Helsinki, Finland
                [55 ]Unit of General Practice, Helsinki University Central Hospital , Helsinki, Finland
                [56 ]K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo , Oslo, Norway
                [57 ]Department of Psychology, University of Oslo , Oslo, Norway
                [58 ]Survey Research Center, Institute for Social Research, University of Michigan , Ann Arbor, MI, USA
                [59 ]Robertson Center for Biostatistics , Glasgow, UK
                [60 ]Generation Scotland, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital , Edinburgh, UK
                [61 ]Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD, USA
                [62 ]Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center , Jackson, MS, USA
                [63 ]Intramural Research Program National Institutes on Aging, National Institutes of Health , Bethesda, MD, USA
                [64 ]Department of Epidemiology, University of North Carolina Gillings School of Global Public Health , Chapel Hill, NC, USA
                [65 ]Neuropsychiatric Institute, Prince of Wales Hospital , Sydney, NSW, Australia
                [66 ]Department of Neurology, Mayo Clinic , Rochester, MN, USA
                [67 ]Neuroscience Research Australia , Randwick, NSW, Australia
                [68 ]School of Medical Sciences, University of New South Wales , Sydney, NSW, Australia
                [69 ]Technische Universität Dresden , Dresden, Germany
                [70 ]Department of Biological and Medical Psychology, University of Bergen , Bergen, Norway
                [71 ]Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital , Bergen, Norway
                [72 ]K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen , Bergen, Norway
                [73 ]Umeå Center for Functional Brain Imaging (UFBI), Umeå University , Umeå, Sweden
                [74 ]Department of Radiation Sciences, Umeå University , Umeå, Sweden
                [75 ]Department of Integrative Medical Biology, Umeå University , Umeå, Sweden
                [76 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus , Cambridge, UK
                [77 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki , Helsinki, Finland
                [78 ]Department of Medical Genetics, University of Helsinki and University Central Hospital , Helsinki, Finland
                [79 ]Karolinska Institutet, Aging Research Center, Stockholm University , Stockholm, Sweden
                [80 ]Faculty of Medicine, Department of Public Health, University of Split , Split, Croatia
                [81 ]Deparment of Epidemiology, University of Washington , Seattle, WA, USA
                [82 ]Deparment of Health Services, University of Washington , Seattle, WA, USA
                [83 ]Group Health Research Unit, Group Health Cooperative , Seattle, WA, USA
                [84 ]Institute for Translational Genomics and Population Sciences Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center , Los Angeles, CA, USA
                [85 ]Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center , Los Angeles, CA, USA
                [86 ]Centre for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz , Graz, Austria
                [87 ]School of Medicine and Public Health, University of Newcastle , Newcastle, NSW, Australia
                [88 ]Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow, UK
                [89 ]Department of Pediatrics, Harbor-UCLA Medical Center , Los Angeles, CA, USA
                [90 ]Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales , Sydney, NSW, Australia
                [91 ]Department of Cardiology, Leiden University Medical Center , Leiden, The Netherlands
                [92 ]Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands
                [93 ]Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center , Jackson, MS, USA
                [94 ]Durrer Center for Cardiogenetic Research , Amsterdam, The Netherlands
                [95 ]Interuniversity Cardiology Institute of the Netherlands , Utrecht, The Netherlands
                [96 ]Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute , Brisbane, QLD, Australia
                [97 ]Dementia Collaborative Research Centre, University of New South Wales , Sydney, NSW, Australia
                [98 ]Department of Radiology, Erasmus University Medical Center , Rotterdam, The Netherlands
                [99 ]ARC, Karolinska Institutet, Stockholm and UFBI, Umeå University , Umeå, Sweden
                [100 ]Neuroscience Research Australia , Sydney, NSW, Australia
                [101 ]Faculty of Medicine, University of New South Wales , Sydney, NSW, Australia
                [102 ]Stroke and Ageing Research, Medicine, Southern Clinical School, Monash University , Melbourne, VIC, Australia
                [103 ]Alzheimer Scotland Dementia Research Centre, University of Edinburgh , Edinburgh, UK
                [104 ]Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic , Rochester, MN, USA
                [105 ]Department of Global Health, University of Washington , Seattle, WA, USA
                Author notes
                [* ]Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh , 7 George Square, Edinburgh EH8 9JZ, Scotland, UK. E-mail: i.deary@ 123456ed.ac.uk
                Article
                mp2014188
                10.1038/mp.2014.188
                4356746
                25644384
                b8a09779-60ac-4995-9bd0-e28d4844cf5c
                Copyright © 2015 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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