GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

doi:10.1038/mp.2016.244

Meta-Analysis

. 2017 Mar;22(3):336-345.

doi: 10.1038/mp.2016.244. Epub 2017 Jan 17.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

J W Trampush¹, M L Z Yang², J Yu^{1

3}, E Knowles⁴, G Davies^{5

6}, D C Liewald⁶, J M Starr^{5

7}, S Djurovic^{8

9}, I Melle^{9

10}, K Sundet^{10

11}, A Christoforou^{9

12}, I Reinvang¹¹, P DeRosse^{1

3}, A J Lundervold¹³, V M Steen^{9

12}, T Espeseth^{10

11}, K Räikkönen¹⁴, E Widen¹⁵, A Palotie^{15

16

17}, J G Eriksson^{18

19

20

21}, I Giegling²², B Konte²², P Roussos^{23

24

25}, S Giakoumaki²⁶, K E Burdick^{23

25}, A Payton^{27

28}, W Ollier²⁹, M Horan³⁰, O Chiba-Falek³¹, D K Attix^{31

32}, A C Need³³, E T Cirulli³⁴, A N Voineskos³⁵, N C Stefanis^{36

37

38}, D Avramopoulos^{39

40}, A Hatzimanolis^{36

37

38}, D E Arking⁴⁰, N Smyrnis^{36

37}, R M Bilder⁴¹, N A Freimer⁴¹, T D Cannon⁴², E London⁴¹, R A Poldrack⁴³, F W Sabb⁴⁴, E Congdon⁴¹, E D Conley⁴⁵, M A Scult⁴⁶, D Dickinson⁴⁷, R E Straub⁴⁸, G Donohoe⁴⁹, D Morris⁵⁰, A Corvin⁵⁰, M Gill⁵⁰, A R Hariri⁴⁶, D R Weinberger⁴⁸, N Pendleton^{29

30}, P Bitsios⁵¹, D Rujescu²², J Lahti^{14

52}, S Le Hellard^{9

12}, M C Keller⁵³, O A Andreassen^{9

10

54}, I J Deary^{5

6}, D C Glahn⁴, A K Malhotra^{1

3

55}, T Lencz^{1

3

55}

Affiliations

¹ Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
² Institute of Mental Health, Singapore, Singapore.
³ Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁶ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁷ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
⁸ Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway.
⁹ NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
¹⁰ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹¹ Department of Psychology, University of Oslo, Oslo, Norway.
¹² Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
¹³ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
¹⁴ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
¹⁵ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
¹⁷ Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
¹⁸ National Institute for Health and Welfare, Helsinki, Finland.
¹⁹ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
²⁰ Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
²¹ Folkhälsan Research Centre, Helsinki, Finland.
²² Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
²³ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY, USA.
²⁶ Department of Psychology, University of Crete, Rethymno, Greece.
²⁷ Manchester Centre for Audiology and Deafness, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
²⁸ Division of Evolution and Genomic Sciences, School of Biological Sciences, The University of Manchester, Manchester, UK.
²⁹ Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
³⁰ Manchester Medical School, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, UK.
³¹ Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
³² Division of Medical Psychology, Department of Neurology, Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
³³ Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.
³⁴ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁵ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
³⁶ Department of Psychiatry, University of Athens School of Medicine, Eginition Hospital, Athens, Greece.
³⁷ University Mental Health Research Institute, Athens, Greece.
³⁸ Neurobiology Research Institute, Theodor Theohari Cozzika Foundation, Athens, Greece.
³⁹ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁰ Department of Psychiatry and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴¹ UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
⁴² Department of Psychology, Yale University, New Haven, CT, USA.
⁴³ Department of Psychology, Stanford University, Palo Alto, CA, USA.
⁴⁴ Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
⁴⁵ 23andMe, Inc., Mountain View, CA, USA.
⁴⁶ Department of Psychology & Neuroscience, Laboratory of NeuroGenetics, Duke University, Durham, NC, USA.
⁴⁷ Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.
⁴⁸ Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
⁴⁹ Department of Psychology, National University of Ireland, Galway, Ireland.
⁵⁰ Department of Psychiatry, Neuropsychiatric Genetics Research Group, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁵¹ Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
⁵² Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
⁵³ Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
⁵⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵⁵ Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA.

PMID: 28093568
PMCID: PMC5322272
DOI: 10.1038/mp.2016.244

Meta-Analysis

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

J W Trampush et al. Mol Psychiatry. 2017 Mar.

. 2017 Mar;22(3):336-345.

doi: 10.1038/mp.2016.244. Epub 2017 Jan 17.

Authors

Affiliations

¹ Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
² Institute of Mental Health, Singapore, Singapore.
³ Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁶ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁷ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
⁸ Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway.
⁹ NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.
¹⁰ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹¹ Department of Psychology, University of Oslo, Oslo, Norway.
¹² Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
¹³ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
¹⁴ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
¹⁵ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
¹⁷ Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
¹⁸ National Institute for Health and Welfare, Helsinki, Finland.
¹⁹ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
²⁰ Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
²¹ Folkhälsan Research Centre, Helsinki, Finland.
²² Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
²³ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY, USA.
²⁶ Department of Psychology, University of Crete, Rethymno, Greece.
²⁷ Manchester Centre for Audiology and Deafness, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
²⁸ Division of Evolution and Genomic Sciences, School of Biological Sciences, The University of Manchester, Manchester, UK.
²⁹ Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK.
³⁰ Manchester Medical School, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, UK.
³¹ Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
³² Division of Medical Psychology, Department of Neurology, Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
³³ Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.
³⁴ Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁵ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
³⁶ Department of Psychiatry, University of Athens School of Medicine, Eginition Hospital, Athens, Greece.
³⁷ University Mental Health Research Institute, Athens, Greece.
³⁸ Neurobiology Research Institute, Theodor Theohari Cozzika Foundation, Athens, Greece.
³⁹ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁰ Department of Psychiatry and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴¹ UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
⁴² Department of Psychology, Yale University, New Haven, CT, USA.
⁴³ Department of Psychology, Stanford University, Palo Alto, CA, USA.
⁴⁴ Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
⁴⁵ 23andMe, Inc., Mountain View, CA, USA.
⁴⁶ Department of Psychology & Neuroscience, Laboratory of NeuroGenetics, Duke University, Durham, NC, USA.
⁴⁷ Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.
⁴⁸ Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
⁴⁹ Department of Psychology, National University of Ireland, Galway, Ireland.
⁵⁰ Department of Psychiatry, Neuropsychiatric Genetics Research Group, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁵¹ Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
⁵² Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
⁵³ Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
⁵⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵⁵ Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA.

PMID: 28093568
PMCID: PMC5322272
DOI: 10.1038/mp.2016.244

Erratum in

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.
Trampush JW, Yang MLZ, Yu J, Knowles E, Davies G, Liewald DC, Starr JM, Djurovic S, Melle I, Sundet K, Christoforou A, Reinvang I, DeRosse P, Lundervold AJ, Steen VM, Espeseth T, Räikkönen K, Widen E, Palotie A, Eriksson JG, Giegling I, Konte B, Roussos P, Giakoumaki S, Burdick KE, Payton A, Ollier W, Horan M, Chiba-Falek O, Attix DK, Need AC, Cirulli ET, Voineskos AN, Stefanis NC, Avramopoulos D, Hatzimanolis A, Arking DE, Smyrnis N, Bilder RM, Freimer NA, Cannon TD, London E, Poldrack RA, Sabb FW, Congdon E, Conley ED, Scult MA, Dickinson D, Straub RE, Donohoe G, Morris D, Corvin A, Gill M, Hariri AR, Weinberger DR, Pendleton N, Bitsios P, Rujescu D, Lahti J, Le Hellard S, Keller MC, Andreassen OA, Deary IJ, Glahn DC, Malhotra AK, Lencz T. Trampush JW, et al. Mol Psychiatry. 2017 Nov;22(11):1651-1652. doi: 10.1038/mp.2017.197. Epub 2017 Sep 12. Mol Psychiatry. 2017. PMID: 29068436 Free PMC article.

Abstract

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10^-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Manhattan plot depicting results of genome-wide association study meta-analysis for general cognitive function. Green arrows indicate loci attaining genome-wide significance (red line, P<5 × 10⁻⁸). Gray arrow indicates locus at chromosome 17q21.31 approaching genome-wide significance.

**Figure 2**
Region plots depicting genome-wide significant loci on Chromosome 2 (top) and Chromosome 1 (bottom). Local linkage disequilibrium (r²) is color-coded as shown in the legend, and local recombination rate is depicted by the bright blue peaks (magnitude indicated by the right-hand y axis).

See this image and copyright information in PMC

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References

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[1] Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 2014; 46: 1173–1186. - PMC - PubMed

[2] Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 2014; 46: 1173–1186. - PMC - PubMed

[3] Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206. - PMC - PubMed

[4] Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206. - PMC - PubMed

[5] Deary IJ, Johnson W, Houlihan LM. Genetic foundations of human intelligence. Hum Genet 2009; 126: 215–232. - PubMed

[6] Deary IJ, Johnson W, Houlihan LM. Genetic foundations of human intelligence. Hum Genet 2009; 126: 215–232. - PubMed

[7] Davies G, Tenesa A, Payton A, Yang J, Harris SE, Liewald D et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol Psychiatry 2011; 16: 996–1005. - PMC - PubMed

[8] Davies G, Tenesa A, Payton A, Yang J, Harris SE, Liewald D et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol Psychiatry 2011; 16: 996–1005. - PMC - PubMed

[9] Lencz T, Knowles E, Davies G, Guha S, Liewald DC, Starr JM et al. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry 2013; 19: 168–174. - PMC - PubMed

[10] Lencz T, Knowles E, Davies G, Guha S, Liewald DC, Starr JM et al. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry 2013; 19: 168–174. - PMC - PubMed

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GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

Affiliations

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

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