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Common genetic variants influence human subcortical brain structures.

ABSTRACT: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08?×?10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

SUBMITTER: Hibar DP

PROVIDER: S-EPMC4393366 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Common genetic variants influence human subcortical brain structures.

Hibar Derrek P DP Stein Jason L JL Renteria Miguel E ME Arias-Vasquez Alejandro A Desrivières Sylvane S Jahanshad Neda N Toro Roberto R Wittfeld Katharina K Abramovic Lucija L Andersson Micael M Aribisala Benjamin S BS Armstrong Nicola J NJ Bernard Manon M Bohlken Marc M MM Boks Marco P MP Bralten Janita J Brown Andrew A AA Chakravarty M Mallar MM Chen Qiang Q Ching Christopher R K CR Cuellar-Partida Gabriel G den Braber Anouk A Giddaluru Sudheer S Goldman Aaron L AL Grimm Oliver O Guadalupe Tulio T Hass Johanna J Woldehawariat Girma G Holmes Avram J AJ Hoogman Martine M Janowitz Deborah D Jia Tianye T Kim Sungeun S Klein Marieke M Kraemer Bernd B Lee Phil H PH Olde Loohuis Loes M LM Luciano Michelle M Macare Christine C Mather Karen A KA Mattheisen Manuel M Milaneschi Yuri Y Nho Kwangsik K Papmeyer Martina M Ramasamy Adaikalavan A Risacher Shannon L SL Roiz-Santiañez Roberto R Rose Emma J EJ Salami Alireza A Sämann Philipp G PG Schmaal Lianne L Schork Andrew J AJ Shin Jean J Strike Lachlan T LT Teumer Alexander A van Donkelaar Marjolein M J MM van Eijk Kristel R KR Walters Raymond K RK Walters Raymond K RK Westlye Lars T LT Whelan Christopher D CD Winkler Anderson M AM Zwiers Marcel P MP Alhusaini Saud S Athanasiu Lavinia L Ehrlich Stefan S Hakobjan Marina M H MM Hartberg Cecilie B CB Haukvik Unn K UK Heister Angelien J G A M AJ Hoehn David D Kasperaviciute Dalia D Liewald David C M DC Lopez Lorna M LM Makkinje Remco R R RR Matarin Mar M Naber Marlies A M MA McKay D Reese DR Needham Margaret M Nugent Allison C AC Pütz Benno B Royle Natalie A NA Shen Li L Sprooten Emma E Trabzuni Daniah D van der Marel Saskia S L SS van Hulzen Kimm J E KJ Walton Esther E Wolf Christiane C Almasy Laura L Ames David D Arepalli Sampath S Assareh Amelia A AA Bastin Mark E ME Brodaty Henry H Bulayeva Kazima B KB Carless Melanie A MA Cichon Sven S Corvin Aiden A Curran Joanne E JE Czisch Michael M de Zubicaray Greig I GI Dillman Allissa A Duggirala Ravi R Dyer Thomas D TD Erk Susanne S Fedko Iryna O IO Ferrucci Luigi L Foroud Tatiana M TM Fox Peter T PT Fukunaga Masaki M Gibbs J Raphael JR Göring Harald H H HH Green Robert C RC Guelfi Sebastian S Hansell Narelle K NK Hartman Catharina A CA Hegenscheid Katrin K Heinz Andreas A Hernandez Dena G DG Heslenfeld Dirk J DJ Hoekstra Pieter J PJ Holsboer Florian F Homuth Georg G Hottenga Jouke-Jan JJ Ikeda Masashi M Jack Clifford R CR Jenkinson Mark M Johnson Robert R Kanai Ryota R Keil Maria M Kent Jack W JW Kochunov Peter P Kwok John B JB Lawrie Stephen M SM Liu Xinmin X Longo Dan L DL McMahon Katie L KL Meisenzahl Eva E Melle Ingrid I Mohnke Sebastian S Montgomery Grant W GW Mostert Jeanette C JC Mühleisen Thomas W TW Nalls Michael A MA Nichols Thomas E TE Nilsson Lars G LG Nöthen Markus M MM Ohi Kazutaka K Olvera Rene L RL Perez-Iglesias Rocio R Pike G Bruce GB Potkin Steven G SG Reinvang Ivar I Reppermund Simone S Rietschel Marcella M Romanczuk-Seiferth Nina N Rosen Glenn D GD Rujescu Dan D Schnell Knut K Schofield Peter R PR Smith Colin C Steen Vidar M VM Sussmann Jessika E JE Thalamuthu Anbupalam A Toga Arthur W AW Traynor Bryan J BJ Troncoso Juan J Turner Jessica A JA Valdés Hernández Maria C MC van 't Ent Dennis D van der Brug Marcel M van der Wee Nic J A NJ van Tol Marie-Jose MJ Veltman Dick J DJ Wassink Thomas H TH Westman Eric E Zielke Ronald H RH Zonderman Alan B AB Ashbrook David G DG Hager Reinmar R Lu Lu L McMahon Francis J FJ Morris Derek W DW Williams Robert W RW Brunner Han G HG Buckner Randy L RL Buitelaar Jan K JK Cahn Wiepke W Calhoun Vince D VD Cavalleri Gianpiero L GL Crespo-Facorro Benedicto B Dale Anders M AM Davies Gareth E GE Delanty Norman N Depondt Chantal C Djurovic Srdjan S Drevets Wayne C WC Espeseth Thomas T Gollub Randy L RL Ho Beng-Choon BC Hoffmann Wolfgang W Hosten Norbert N Kahn René S RS Le Hellard Stephanie S Meyer-Lindenberg Andreas A Müller-Myhsok Bertram B Nauck Matthias M Nyberg Lars L Pandolfo Massimo M Penninx Brenda W J H BW Roffman Joshua L JL Sisodiya Sanjay M SM Smoller Jordan W JW van Bokhoven Hans H van Haren Neeltje E M NE Völzke Henry H Walter Henrik H Weiner Michael W MW Wen Wei W White Tonya T Agartz Ingrid I Andreassen Ole A OA Blangero John J Boomsma Dorret I DI Brouwer Rachel M RM Cannon Dara M DM Cookson Mark R MR de Geus Eco J C EJ Deary Ian J IJ Donohoe Gary G Fernández Guillén G Fisher Simon E SE Francks Clyde C Glahn David C DC Grabe Hans J HJ Gruber Oliver O Hardy John J Hashimoto Ryota R Hulshoff Pol Hilleke E HE Jönsson Erik G EG Kloszewska Iwona I Lovestone Simon S Mattay Venkata S VS Mecocci Patrizia P McDonald Colm C McIntosh Andrew M AM Ophoff Roel A RA Paus Tomas T Pausova Zdenka Z Ryten Mina M Sachdev Perminder S PS Saykin Andrew J AJ Simmons Andy A Singleton Andrew A Soininen Hilkka H Wardlaw Joanna M JM Weale Michael E ME Weinberger Daniel R DR Adams Hieab H H HH Launer Lenore J LJ Seiler Stephan S Schmidt Reinhold R Chauhan Ganesh G Satizabal Claudia L CL Becker James T JT Yanek Lisa L van der Lee Sven J SJ Ebling Maritza M Fischl Bruce B Longstreth W T WT Greve Douglas D Schmidt Helena H Nyquist Paul P Vinke Louis N LN van Duijn Cornelia M CM Xue Luting L Mazoyer Bernard B Bis Joshua C JC Gudnason Vilmundur V Seshadri Sudha S Ikram M Arfan MA Martin Nicholas G NG Wright Margaret J MJ Schumann Gunter G Franke Barbara B Thompson Paul M PM Medland Sarah E SE

Nature 20150121 7546

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magneti ...[more]

PMID: 25607358

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Project description:The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression.

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Common genetic variants influence human subcortical brain structures.

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Common genetic variants influence human subcortical brain structures.

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