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

Max Lam; Joey W Trampush; Jin Yu; Emma Knowles; Srdjan Djurovic; Ingrid Melle; Kjetil Sundet; Andrea Christoforou; Ivar Reinvang; Pamela DeRosse; Astri J Lundervold; Vidar M Steen; Thomas Espeseth; Katri Räikkönen; Elisabeth Widen; Aarno Palotie; Johan G Eriksson; Ina Giegling; Bettina Konte; Panos Roussos; Stella Giakoumaki; Katherine E Burdick; Antony Payton; William Ollier; Ornit Chiba-Falek; Deborah K Attix; Anna C Need; Elizabeth T Cirulli; Aristotle N Voineskos; Nikos C Stefanis; Dimitrios Avramopoulos; Alex Hatzimanolis; Dan E Arking; Nikolaos Smyrnis; Robert M Bilder; Nelson A Freimer; Tyrone D Cannon; Edythe London; Russell A Poldrack; Fred W Sabb; Eliza Congdon; Emily Drabant Conley; Matthew A Scult; Dwight Dickinson; Richard E Straub; Gary Donohoe; Derek Morris; Aiden Corvin; Michael Gill; Ahmad R Hariri; Daniel R Weinberger; Neil Pendleton; Panos Bitsios; Dan Rujescu; Jari Lahti; Stephanie Le Hellard; Matthew C Keller; Ole A Andreassen; David C Glahn; Anil K Malhotra; Todd Lencz

doi:10.1017/thg.2018.46

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

Twin Res Hum Genet. 2018 Oct;21(5):394-397. doi: 10.1017/thg.2018.46. Epub 2018 Jul 13.

Authors

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

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.

Publication types

Comment

MeSH terms

Cognition
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Nootropic Agents*
Polymorphism, Single Nucleotide

Substances

Nootropic Agents

Abstract

Publication types

MeSH terms

Substances

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