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. 2016 Dec;19(12):1569-1582.
doi: 10.1038/nn.4398. Epub 2016 Oct 3.

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Hieab H H Adams  1   2 , Derrek P Hibar  3 , Vincent Chouraki  4   5   6 , Jason L Stein  3   7 , Paul A Nyquist  8 , Miguel E Rentería  9 , Stella Trompet  10 , Alejandro Arias-Vasquez  11   12   13   14 , Sudha Seshadri  4   6 , Sylvane Desrivières  15 , Ashley H Beecham  16   17 , Neda Jahanshad  3 , Katharina Wittfeld  18   19 , Sven J Van der Lee  1 , Lucija Abramovic  20 , Saud Alhusaini  21   22 , Najaf Amin  1 , Micael Andersson  23 , Konstantinos Arfanakis  24   25   26 , Benjamin S Aribisala  27   28   29 , Nicola J Armstrong  30   31 , Lavinia Athanasiu  32   33 , Tomas Axelsson  34 , Alexa Beiser  4   6   35 , Manon Bernard  36 , Joshua C Bis  37 , Laura M E Blanken  38   39 , Susan H Blanton  16   17 , Marc M Bohlken  20 , Marco P Boks  20 , Janita Bralten  11   14 , Adam M Brickman  40   41   42 , Owen Carmichael  43 , M Mallar Chakravarty  44   45 , Ganesh Chauhan  46 , Qiang Chen  47 , Christopher R K Ching  3   48 , Gabriel Cuellar-Partida  9 , Anouk Den Braber  49 , Nhat Trung Doan  32 , Stefan Ehrlich  50   51   52 , Irina Filippi  53   54 , Tian Ge  52   55   56   57 , Sudheer Giddaluru  58   59 , Aaron L Goldman  47 , Rebecca F Gottesman  60 , Corina U Greven  13   61   62 , Oliver Grimm  63 , Michael E Griswold  64 , Tulio Guadalupe  65   66 , Johanna Hass  67 , Unn K Haukvik  32   68 , Saima Hilal  69   70 , Edith Hofer  71   72 , David Hoehn  73 , Avram J Holmes  51   74 , Martine Hoogman  11   14 , Deborah Janowitz  19 , Tianye Jia  15 , Dalia Kasperaviciute  75   76 , Sungeun Kim  77   78   79 , Marieke Klein  11   14 , Bernd Kraemer  80 , Phil H Lee  51   55   56   57   81 , Jiemin Liao  82 , David C M Liewald  83 , Lorna M Lopez  83 , Michelle Luciano  83 , Christine Macare  15 , Andre Marquand  14   84 , Mar Matarin  75   85 , Karen A Mather  30 , Manuel Mattheisen  86   87   88 , Bernard Mazoyer  89 , David R McKay  90   91 , Rebekah McWhirter  92 , Yuri Milaneschi  93 , Nazanin Mirza-Schreiber  73 , Ryan L Muetzel  38   39 , Susana Muñoz Maniega  27   29   83 , Kwangsik Nho  77   78   79 , Allison C Nugent  94 , Loes M Olde Loohuis  95 , Jaap Oosterlaan  96 , Martina Papmeyer  97   98 , Irene Pappa  38   99 , Lukas Pirpamer  71 , Sara Pudas  23 , Benno Pütz  73 , Kumar B Rajan  100 , Adaikalavan Ramasamy  85   101   102 , Jennifer S Richards  13   14   61 , Shannon L Risacher  77   79 , Roberto Roiz-Santiañez  103   104 , Nanda Rommelse  12   14   61 , Emma J Rose  105 , Natalie A Royle  27   29   83   106 , Tatjana Rundek  107   108 , Philipp G Sämann  73 , Claudia L Satizabal  4   6 , Lianne Schmaal  109   110   111 , Andrew J Schork  112   113 , Li Shen  77   78   79 , Jean Shin  36 , Elena Shumskaya  11   14   84 , Albert V Smith  114   115 , Emma Sprooten  90   91   97   116 , Lachlan T Strike  9   117 , Alexander Teumer  118 , Russell Thomson  119 , Diana Tordesillas-Gutierrez  104   120 , Roberto Toro  121 , Daniah Trabzuni  85   122 , Dhananjay Vaidya  123 , Jeroen Van der Grond  124 , Dennis Van der Meer  125 , Marjolein M J Van Donkelaar  11   14 , Kristel R Van Eijk  126 , Theo G M Van Erp  127 , Daan Van Rooij  13   14   125 , Esther Walton  67 , Lars T Westlye  33   128 , Christopher D Whelan  3   22 , Beverly G Windham  129 , Anderson M Winkler  90   130 , Girma Woldehawariat  94 , Christiane Wolf  131 , Thomas Wolfers  11   14 , Bing Xu  15 , Lisa R Yanek  123 , Jingyun Yang  25   132 , Alex Zijdenbos  133 , Marcel P Zwiers  14   84 , Ingrid Agartz  32   68   134 , Neelum T Aggarwal  25   100   132 , Laura Almasy  135   136   137 , David Ames  138   139 , Philippe Amouyel  5 , Ole A Andreassen  32   33 , Sampath Arepalli  140 , Amelia A Assareh  30 , Sandra Barral  40 , Mark E Bastin  27   29   83   106 , Diane M Becker  123 , James T Becker  141 , David A Bennett  25   132 , John Blangero  135 , Hans van Bokhoven  11   14 , Dorret I Boomsma  49 , Henry Brodaty  30   142 , Rachel M Brouwer  20 , Han G Brunner  11   14   143 , Randy L Buckner  51   144 , Jan K Buitelaar  13   14   61 , Kazima B Bulayeva  145 , Wiepke Cahn  20 , Vince D Calhoun  146   147 , Dara M Cannon  94   148 , Gianpiero L Cavalleri  22 , Christopher Chen  69   70 , Ching-Yu Cheng  82   149   150 , Sven Cichon  151   152   153 , Mark R Cookson  140 , Aiden Corvin  105 , Benedicto Crespo-Facorro  103   104 , Joanne E Curran  135 , Michael Czisch  73 , Anders M Dale  154   155   156   157   158 , Gareth E Davies  159   160   56   161 , Eco J C De Geus  49 , Philip L De Jager  56   161   162 , Greig I de Zubicaray  163 , Norman Delanty  22   164 , Chantal Depondt  165 , Anita L DeStefano  6   59 , Allissa Dillman  140 , Srdjan Djurovic  58   166 , Gary Donohoe  167   168 , Wayne C Drevets  94   169 , Ravi Duggirala  135 , Thomas D Dyer  135 , Susanne Erk  170 , Thomas Espeseth  33   128 , Denis A Evans  100 , Iryna O Fedko  49 , Guillén Fernández  13   14 , Luigi Ferrucci  171 , Simon E Fisher  14   65 , Debra A Fleischman  25   132   172 , Ian Ford  173 , Tatiana M Foroud  78   174 , Peter T Fox  175 , Clyde Francks  14   65 , Masaki Fukunaga  176 , J Raphael Gibbs  85   140 , David C Glahn  90   91 , Randy L Gollub  51   52   56 , Harald H H Göring  135 , Hans J Grabe  19 , Robert C Green  56   177 , Oliver Gruber  80 , Vilmundur Gudnason  114   115 , Sebastian Guelfi  85 , Narelle K Hansell  9   117 , John Hardy  85 , Catharina A Hartman  125 , Ryota Hashimoto  178   179 , Katrin Hegenscheid  180 , Andreas Heinz  170 , Stephanie Le Hellard  58   59 , Dena G Hernandez  85   140   181 , Dirk J Heslenfeld  182 , Beng-Choon Ho  183 , Pieter J Hoekstra  125 , Wolfgang Hoffmann  18   118 , Albert Hofman  1 , Florian Holsboer  73   184 , Georg Homuth  185 , Norbert Hosten  180 , Jouke-Jan Hottenga  49 , Hilleke E Hulshoff Pol  20 , Masashi Ikeda  186 , M Kamran Ikram  1   69   70   82   149 , Clifford R Jack Jr  187 , Mark Jenkinson  130 , Robert Johnson  188 , Erik G Jönsson  32   130 , J Wouter Jukema  10 , René S Kahn  20 , Ryota Kanai  189   190   191 , Iwona Kloszewska  192 , David S Knopman  193 , Peter Kochunov  194 , John B Kwok  195   196 , Stephen M Lawrie  97 , Hervé Lemaître  53   54 , Xinmin Liu  94   197 , Dan L Longo  198 , W T Longstreth Jr  199   200 , Oscar L Lopez  201   202 , Simon Lovestone  203   204 , Oliver Martinez  205 , Jean-Luc Martinot  53   54 , Venkata S Mattay  47   60   206 , Colm McDonald  148 , Andrew M McIntosh  83   97 , Katie L McMahon  207 , Francis J McMahon  94 , Patrizia Mecocci  208 , Ingrid Melle  32   33 , Andreas Meyer-Lindenberg  63 , Sebastian Mohnke  170 , Grant W Montgomery  9 , Derek W Morris  167   168 , Thomas H Mosley  129 , Thomas W Mühleisen  148   153 , Bertram Müller-Myhsok  73   209   210 , Michael A Nalls  140 , Matthias Nauck  211   212 , Thomas E Nichols  130   213 , Wiro J Niessen  2   214   215 , Markus M Nöthen  152   216 , Lars Nyberg  23 , Kazutaka Ohi  178 , Rene L Olvera  175 , Roel A Ophoff  20   95 , Massimo Pandolfo  165 , Tomas Paus  217   218   219 , Zdenka Pausova  36   220   221 , Brenda W J H Penninx  111 , G Bruce Pike  222   223 , Steven G Potkin  127 , Bruce M Psaty  200   224   225   226 , Simone Reppermund  30   227 , Marcella Rietschel  63 , Joshua L Roffman  51 , Nina Romanczuk-Seiferth  170 , Jerome I Rotter  228 , Mina Ryten  85   101 , Ralph L Sacco  17   107   108   229 , Perminder S Sachdev  30   230 , Andrew J Saykin  77   79   174 , Reinhold Schmidt  71 , Peter R Schofield  195   196 , Sigurdur Sigurdsson  114 , Andy Simmons  231   232   233 , Andrew Singleton  140 , Sanjay M Sisodiya  75 , Colin Smith  234 , Jordan W Smoller  51   55   56   57 , Hilkka Soininen  235   236 , Velandai Srikanth  237 , Vidar M Steen  58   59 , David J Stott  238 , Jessika E Sussmann  97 , Anbupalam Thalamuthu  30 , Henning Tiemeier  1   39 , Arthur W Toga  239 , Bryan J Traynor  140 , Juan Troncoso  240 , Jessica A Turner  241 , Christophe Tzourio  242 , Andre G Uitterlinden  1   243 , Maria C Valdés Hernández  27   29   83   106 , Marcel Van der Brug  244 , Aad Van der Lugt  2 , Nic J A Van der Wee  245 , Cornelia M Van Duijn  1 , Neeltje E M Van Haren  20 , Dennis Van T Ent  49 , Marie-Jose Van Tol  246 , Badri N Vardarajan  40 , Dick J Veltman  111 , Meike W Vernooij  1   2 , Henry Völzke  118 , Henrik Walter  170 , Joanna M Wardlaw  27   29   83   106 , Thomas H Wassink  247 , Michael E Weale  101 , Daniel R Weinberger  47   248 , Michael W Weiner  249 , Wei Wen  30 , Eric Westman  250 , Tonya White  2   39 , Tien Y Wong  82   145   150 , Clinton B Wright  107   108   229 , H Ronald Zielke  188 , Alan B Zonderman  251 , Ian J Deary  83 , Charles DeCarli  205 , Helena Schmidt  252 , Nicholas G Martin  9 , Anton J M De Craen  253 , Margaret J Wright  117   207 , Lenore J Launer  254 , Gunter Schumann  15 , Myriam Fornage  255 , Barbara Franke  11   12   14 , Stéphanie Debette  4   47   256 , Sarah E Medland  9 , M Arfan Ikram  1   2   257 , Paul M Thompson  3
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Novel genetic loci underlying human intracranial volume identified through genome-wide association

Hieab H H Adams et al. Nat Neurosci. 2016 Dec.

Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

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Figures

Figure 1
Figure 1. Common genetic variants associated with intracranial volume
Manhattan plot where every point represents a single genetic variant plotted according to its genomic position (x-axis) and its –log10(p-value) for association with intracranial volume (y-axis). Variants in blue are genome-wide significant in a previously known locus, whereas red variants reach genome-wide significant for the first time in that locus. The dashed horizontal line represents a significance threshold of p-value < 10−6 and the full horizontal line represents genome-wide significance of p-value < 5 × 10−8. Variants surpassing these thresholds are indicated by larger points.
Figure 2
Figure 2. Regional association and functional annotation of novel genome-wide significant loci
Regional association plots for the five novel genome-wide significant loci of intracranial volume with gene models below (GENCODE version 19). Annotation tracks below from the Roadmap Epigenomics Consortium highlight the genomic region that likely harbors the causal variant(s) (r2 > 0.8 from the top SNP). See Online Methods for detailed track information. Plots were generated using the LocusTrack software (http://gump.qimr.edu.au/general/gabrieC/LocusTrack/).
Figure 3
Figure 3. Meta-analysis of intracranial volume and child head circumference
A ‘twin’ Manhattan plot shows every variant twice: once for the discovery analysis and once for the combined discovery plus replication analysis. The least significant association of the variant-pair is plotted in grey (alternating light and dark between chromosomes). The most significant association of the variant-pair is plotted in red if is from the combined analysis (i.e., the association became more significant after meta-analyzing with the child head circumference GWAS) and in turquoise if it is from the discovery analysis (i.e., the association became less significant after meta-analyzing with the child head circumference GWAS). The dashed horizontal line represents a significance threshold of p-value < 10−6 and the full horizontal line represents genome-wide significance of p-value < 5 × 10−8. Variants surpassing these thresholds are indicated by larger and brighter points.
Figure 4
Figure 4. Enrichment analyses of common variants associated with intracranial volume
Enrichment of subsets of variants for association with intracranial volume: A) by chromosomes, B) by functional subtype, and C) by pathway. See Online Methods for additional information.
Figure 5
Figure 5. Temporal trends of intracranial volume loci during pre- and postnatal brain development
Mean predicted values of standardized head circumference using linear mixed models with age, sex, and the rs199525 or rs138074335 variants. The blue line represents children not carrying the risk allele, purple only a single risk allele, and red with two risk alleles. See Online Methods for additional information. Total sample size is 2,824.
See this image and copyright information in PMC

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