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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

ABSTRACT: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N?=?300,486; age 16-102) and find 148 genome-wide significant independent loci (P?

SUBMITTER: Davies G

PROVIDER: S-EPMC5974083 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Davies Gail G Lam Max M Harris Sarah E SE Trampush Joey W JW Luciano Michelle M Hill W David WD Hagenaars Saskia P SP Ritchie Stuart J SJ Marioni Riccardo E RE Fawns-Ritchie Chloe C Liewald David C M DCM Okely Judith A JA Ahola-Olli Ari V AV Barnes Catriona L K CLK Bertram Lars L Bis Joshua C JC Burdick Katherine E KE Christoforou Andrea A DeRosse Pamela P Djurovic Srdjan S Espeseth Thomas T Giakoumaki Stella S Giddaluru Sudheer S Gustavson Daniel E DE Hayward Caroline C Hofer Edith E Ikram M Arfan MA Karlsson Robert R Knowles Emma E Lahti Jari J Leber Markus M Li Shuo S Mather Karen A KA Melle Ingrid I Morris Derek D Oldmeadow Christopher C Palviainen Teemu T Payton Antony A Pazoki Raha R Petrovic Katja K Reynolds Chandra A CA Sargurupremraj Muralidharan M Scholz Markus M Smith Jennifer A JA Smith Albert V AV Terzikhan Natalie N Thalamuthu Anbupalam A Trompet Stella S van der Lee Sven J SJ Ware Erin B EB Windham B Gwen BG Wright Margaret J MJ Yang Jingyun J Yu Jin J Ames David D Amin Najaf N Amouyel Philippe P Andreassen Ole A OA Armstrong Nicola J NJ Assareh Amelia A AA Attia John R JR Attix Deborah D Avramopoulos Dimitrios D Bennett David A DA Böhmer Anne C AC Boyle Patricia A PA Brodaty Henry H Campbell Harry H Cannon Tyrone D TD Cirulli Elizabeth T ET Congdon Eliza E Conley Emily Drabant ED Corley Janie J Cox Simon R SR Dale Anders M AM Dehghan Abbas A Dick Danielle D Dickinson Dwight D Eriksson Johan G JG Evangelou Evangelos E Faul Jessica D JD Ford Ian I Freimer Nelson A NA Gao He H Giegling Ina I Gillespie Nathan A NA Gordon Scott D SD Gottesman Rebecca F RF Griswold Michael E ME Gudnason Vilmundur V Harris Tamara B TB Hartmann Annette M AM Hatzimanolis Alex A Heiss Gerardo G Holliday Elizabeth G EG Joshi Peter K PK Kähönen Mika M Kardia Sharon L R SLR Karlsson Ida I Kleineidam Luca L Knopman David S DS Kochan Nicole A NA Konte Bettina B Kwok John B JB Le Hellard Stephanie S Lee Teresa T Lehtimäki Terho T Li Shu-Chen SC Lill Christina M CM Liu Tian T Koini Marisa M London Edythe E Longstreth Will T WT Lopez Oscar L OL Loukola Anu A Luck Tobias T Lundervold Astri J AJ Lundquist Anders A Lyytikäinen Leo-Pekka LP Martin Nicholas G NG Montgomery Grant W GW Murray Alison D AD Need Anna C AC Noordam Raymond R Nyberg Lars L Ollier William W Papenberg Goran G Pattie Alison A Polasek Ozren O Poldrack Russell A RA Psaty Bruce M BM Reppermund Simone S Riedel-Heller Steffi G SG Rose Richard J RJ Rotter Jerome I JI Roussos Panos P Rovio Suvi P SP Saba Yasaman Y Sabb Fred W FW Sachdev Perminder S PS Satizabal Claudia L CL Satizabal Claudia L CL Schmid Matthias M Scott Rodney J RJ Scult Matthew A MA Simino Jeannette J Slagboom P Eline PE Smyrnis Nikolaos N Soumaré Aïcha A Stefanis Nikos C NC Stott David J DJ Straub Richard E RE Sundet Kjetil K Taylor Adele M AM Taylor Kent D KD Tzoulaki Ioanna I Tzourio Christophe C Uitterlinden André A Vitart Veronique V Voineskos Aristotle N AN Kaprio Jaakko J Wagner Michael M Wagner Holger H Weinhold Leonie L Wen K Hoyan KH Widen Elisabeth E Yang Qiong Q Zhao Wei W Adams Hieab H H HHH Arking Dan E DE Bilder Robert M RM Bitsios Panos P Boerwinkle Eric E Chiba-Falek Ornit O Corvin Aiden A De Jager Philip L PL Debette Stéphanie S Donohoe Gary G Elliott Paul P Fitzpatrick Annette L AL Gill Michael M Glahn David C DC Hägg Sara S Hansell Narelle K NK Hariri Ahmad R AR Ikram M Kamran MK Jukema J Wouter JW Jukema J Wouter JW Vuoksimaa Eero E Keller Matthew C MC Kremen William S WS Launer Lenore L Lindenberger Ulman U Palotie Aarno A Pedersen Nancy L NL Pendleton Neil N Porteous David J DJ Räikkönen Katri K Raitakari Olli T OT Ramirez Alfredo A Reinvang Ivar I Rudan Igor I Dan Rujescu Schmidt Reinhold R Schmidt Helena H Schofield Peter W PW Schofield Peter R PR Starr John M JM Steen Vidar M VM Trollor Julian N JN Turner Steven T ST Van Duijn Cornelia M CM Villringer Arno A Weinberger Daniel R DR Weir David R DR Wilson James F JF Malhotra Anil A McIntosh Andrew M AM Gale Catharine R CR Seshadri Sudha S Mosley Thomas H TH Bressler Jan J Lencz Todd T Deary Ian J IJ

Nature communications 20180529 1

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10<sup>-8</sup>) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and ...[more]

PMID: 29844566

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Project description:Importance:Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective:To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants:Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n?=?79?757 [cases, 34?486; controls, 45?271]); verbal-numerical reasoning (n?=?36?035) and reaction time (n?=?111?483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n?=?53?949) and COGENT (Cognitive Genomics Consortium) (n?=?27?888). Main Outcomes and Measures:Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results:Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P?=?5.53?×?10-7), general cognitive function (z score, -4.43; P?=?9.42?×?10-6), and verbal-numerical reasoning (z score, -5.43; P?=?5.64?×?10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance:The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

Dataset Information

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Publications

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

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