Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Max Lam¹, Joey W Trampush², Jin Yu³, Emma Knowles⁴, Srdjan Djurovic⁵, Ingrid Melle⁶, Kjetil Sundet⁷, Andrea Christoforou⁸, Ivar Reinvang⁹, Pamela DeRosse³, Astri J Lundervold¹⁰, Vidar M Steen⁶, Thomas Espeseth⁷, Katri Räikkönen¹¹, Elisabeth Widen¹², Aarno Palotie¹², Johan G Eriksson¹³, Ina Giegling¹⁴, Bettina Konte¹⁴, Panos Roussos¹⁵, Stella Giakoumaki¹⁶, Katherine E Burdick¹⁴, Antony Payton¹⁷, William Ollier¹⁷, Ornit Chiba-Falek¹⁸, Deborah K Attix¹⁸, Anna C Need¹⁹, Elizabeth T Cirulli²⁰, Aristotle N Voineskos²¹, Nikos C Stefanis²², Dimitrios Avramopoulos²³, Alex Hatzimanolis²², Dan E Arking²⁴, Nikolaos Smyrnis²², Robert M Bilder²⁵, Nelson A Freimer²⁵, Tyrone D Cannon²⁶, Edythe London²⁵, Russell A Poldrack²⁷, Fred W Sabb²⁸, Eliza Congdon²⁵, Emily Drabant Conley²⁹, Matthew A Scult³⁰, Dwight Dickinson³¹, Richard E Straub³², Gary Donohoe³³, Derek Morris³³, Aiden Corvin³⁴, Michael Gill³⁴, Ahmad R Hariri³⁰, Daniel R Weinberger³², Neil Pendleton³⁵, Panos Bitsios³⁶, Dan Rujescu¹⁴, Jari Lahti¹¹, Stephanie Le Hellard⁶, Matthew C Keller³⁷, Ole A Andreassen⁶, David C Glahn⁴, Anil K Malhotra³, Todd Lencz³

Affiliations

¹ Institute of Mental Health,Singapore.
² BrainWorkup,LLC,Los Angeles,CA,USA.
³ Division of Psychiatry Research,Zucker Hillside Hospital,Glen Oaks,NY,USA.
⁴ Department of Psychiatry,Yale University School of Medicine,New Haven,CT,USA.
⁵ Department of Medical Genetics,Oslo University Hospital,University of Bergen,Oslo,Norway.
⁶ NORMENT,K. G. Jebsen Centre for Psychosis Research,University of Bergen,Bergen,Norway.
⁷ Division of Mental Health and Addiction,Oslo University Hospital,Oslo,Norway.
⁸ Dr. Einar Martens Research Group for Biological Psychiatry,Center for Medical Genetics and Molecular Medicine,Haukeland University Hospital,Bergen,Norway.
⁹ Department of Psychology,University of Oslo,Oslo,Norway.
¹⁰ Department of Biological and Medical Psychology,University of Bergen,Norway.
¹¹ Institute of Behavioural Sciences,University of Helsinki,Helsinki,Finland.
¹² Institute for Molecular Medicine Finland (FIMM),University of Helsinki,Finland.
¹³ Department of General Practice,University of Helsinki and Helsinki University Hospital,Helsinki,Finland.
¹⁴ Department of Psychiatry,Martin Luther University of Halle-Wittenberg,Halle,Germany.
¹⁵ Department of Psychiatry,Icahn School of Medicine at Mount Sinai,New York,NY,USA.
¹⁶ Department of Psychology,University of Crete,Rethymnon,Greece.
¹⁷ Centre for Epidemiology,Division of Population Health,Health Services Research & Primary Care,The University of Manchester,Manchester,UK.
¹⁸ Department of Neurology,Bryan Alzheimer's Disease Research Center,and Center for Genomic and Computational Biology,Duke University Medical Center,Durham,NC,USA.
¹⁹ Division of Brain Sciences,Department of Medicine,Imperial College,London,UK.
²⁰ Human Longevity, Inc.,Durham,NC,USA.
²¹ Campbell Family Mental Health Institute,Centre for Addiction and Mental Health,University of Toronto,Toronto,Canada.
²² Department of Psychiatry,National and Kapodistrian University of Athens Medical School,Eginition Hospital,Athens,Greece.
²³ Department of Psychiatry,Johns Hopkins University School of Medicine,Baltimore,MD,USA.
²⁴ McKusick-Nathans Institute of Genetic Medicine,Johns Hopkins University School of Medicine,Baltimore,MD,USA.
²⁵ UCLA Semel Institute for Neuroscience and Human Behavior,Los Angeles,CA,USA.
²⁶ Department of Psychology,Yale University,New Haven,CT,USA.
²⁷ Department of Psychology,Stanford University,Palo Alto,CA,USA.
²⁸ Robert and Beverly Lewis Center for Neuroimaging,University of Oregon,Eugene,OR,USA.
²⁹ 23 and Me, Inc.,Mountain View,CA,USA.
³⁰ Laboratory of NeuroGenetics,Department of Psychology & Neuroscience,Duke University,Durham,NC,USA.
³¹ Clinical and Translational Neuroscience Branch,Intramural Research Program,National Institute of Mental Health, National Institutes of Health,Bethesda,MD,USA.
³² Lieber Institute for Brain Development,Johns Hopkins University Medical Campus,Baltimore,MD,USA.
³³ Neuroimaging,Cognition & Genomics (NICOG) Centre,School of Psychology and Discipline of Biochemistry,National University of Ireland,Galway,Ireland.
³⁴ Neuropsychiatric Genetics Research Group,Department of Psychiatry and Trinity College Institute of Neuroscience,Trinity College Dublin,Dublin,Ireland.
³⁵ Division of Neuroscience and Experimental Psychology/School of Biological Sciences,Faculty of Biology Medicine and Health,University of Manchester,Manchester Academic Health Science Centre,Salford Royal NHS Foundation Trust,Manchester,UK.
³⁶ Department of Psychiatry and Behavioral Sciences,Faculty of Medicine,University of Crete,Heraklion,Greece.
³⁷ Institute for Behavioral Genetics, University of Colorado,Boulder,CO,USA.

PMID: 30001766
DOI: 10.1017/thg.2018.46

Comment

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Max Lam et al. Twin Res Hum Genet. 2018 Oct.

. 2018 Oct;21(5):394-397.

doi: 10.1017/thg.2018.46. Epub 2018 Jul 13.

Authors

Affiliations

¹ Institute of Mental Health,Singapore.
² BrainWorkup,LLC,Los Angeles,CA,USA.
³ Division of Psychiatry Research,Zucker Hillside Hospital,Glen Oaks,NY,USA.
⁴ Department of Psychiatry,Yale University School of Medicine,New Haven,CT,USA.
⁵ Department of Medical Genetics,Oslo University Hospital,University of Bergen,Oslo,Norway.
⁶ NORMENT,K. G. Jebsen Centre for Psychosis Research,University of Bergen,Bergen,Norway.
⁷ Division of Mental Health and Addiction,Oslo University Hospital,Oslo,Norway.
⁸ Dr. Einar Martens Research Group for Biological Psychiatry,Center for Medical Genetics and Molecular Medicine,Haukeland University Hospital,Bergen,Norway.
⁹ Department of Psychology,University of Oslo,Oslo,Norway.
¹⁰ Department of Biological and Medical Psychology,University of Bergen,Norway.
¹¹ Institute of Behavioural Sciences,University of Helsinki,Helsinki,Finland.
¹² Institute for Molecular Medicine Finland (FIMM),University of Helsinki,Finland.
¹³ Department of General Practice,University of Helsinki and Helsinki University Hospital,Helsinki,Finland.
¹⁴ Department of Psychiatry,Martin Luther University of Halle-Wittenberg,Halle,Germany.
¹⁵ Department of Psychiatry,Icahn School of Medicine at Mount Sinai,New York,NY,USA.
¹⁶ Department of Psychology,University of Crete,Rethymnon,Greece.
¹⁷ Centre for Epidemiology,Division of Population Health,Health Services Research & Primary Care,The University of Manchester,Manchester,UK.
¹⁸ Department of Neurology,Bryan Alzheimer's Disease Research Center,and Center for Genomic and Computational Biology,Duke University Medical Center,Durham,NC,USA.
¹⁹ Division of Brain Sciences,Department of Medicine,Imperial College,London,UK.
²⁰ Human Longevity, Inc.,Durham,NC,USA.
²¹ Campbell Family Mental Health Institute,Centre for Addiction and Mental Health,University of Toronto,Toronto,Canada.
²² Department of Psychiatry,National and Kapodistrian University of Athens Medical School,Eginition Hospital,Athens,Greece.
²³ Department of Psychiatry,Johns Hopkins University School of Medicine,Baltimore,MD,USA.
²⁴ McKusick-Nathans Institute of Genetic Medicine,Johns Hopkins University School of Medicine,Baltimore,MD,USA.
²⁵ UCLA Semel Institute for Neuroscience and Human Behavior,Los Angeles,CA,USA.
²⁶ Department of Psychology,Yale University,New Haven,CT,USA.
²⁷ Department of Psychology,Stanford University,Palo Alto,CA,USA.
²⁸ Robert and Beverly Lewis Center for Neuroimaging,University of Oregon,Eugene,OR,USA.
²⁹ 23 and Me, Inc.,Mountain View,CA,USA.
³⁰ Laboratory of NeuroGenetics,Department of Psychology & Neuroscience,Duke University,Durham,NC,USA.
³¹ Clinical and Translational Neuroscience Branch,Intramural Research Program,National Institute of Mental Health, National Institutes of Health,Bethesda,MD,USA.
³² Lieber Institute for Brain Development,Johns Hopkins University Medical Campus,Baltimore,MD,USA.
³³ Neuroimaging,Cognition & Genomics (NICOG) Centre,School of Psychology and Discipline of Biochemistry,National University of Ireland,Galway,Ireland.
³⁴ Neuropsychiatric Genetics Research Group,Department of Psychiatry and Trinity College Institute of Neuroscience,Trinity College Dublin,Dublin,Ireland.
³⁵ Division of Neuroscience and Experimental Psychology/School of Biological Sciences,Faculty of Biology Medicine and Health,University of Manchester,Manchester Academic Health Science Centre,Salford Royal NHS Foundation Trust,Manchester,UK.
³⁶ Department of Psychiatry and Behavioral Sciences,Faculty of Medicine,University of Crete,Heraklion,Greece.
³⁷ Institute for Behavioral Genetics, University of Colorado,Boulder,CO,USA.

PMID: 30001766
DOI: 10.1017/thg.2018.46

Abstract

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Keywords: GWAS; calcium channel; cerebellum; gene expression; general cognitive ability; neurodevelopment; nootropics; potassium channel; synapse.

PubMed Disclaimer

Comment in

A Further Comment on 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' by Lam et al.
Hill WD. Hill WD. Twin Res Hum Genet. 2018 Dec;21(6):538-545. doi: 10.1017/thg.2018.55. Epub 2018 Oct 8. Twin Res Hum Genet. 2018. PMID: 30293537 Free PMC article.

Comment on

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.
Lam M, Trampush JW, 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, 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. Lam M, et al. Cell Rep. 2017 Nov 28;21(9):2597-2613. doi: 10.1016/j.celrep.2017.11.028. Cell Rep. 2017. PMID: 29186694 Free PMC article.
Comment on 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' by Lam et al.
Hill WD. Hill WD. Twin Res Hum Genet. 2018 Apr;21(2):84-88. doi: 10.1017/thg.2018.12. Epub 2018 Mar 19. Twin Res Hum Genet. 2018. PMID: 29551100

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Affiliations

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018)

Authors

Affiliations

Abstract

Comment in

Comment on

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources