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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
Affiliations

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.

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References

    1. Bartley AJ, Jones DW, Weinberger DR. Genetic variability of human brain size and cortical gyral patterns. Brain. 1997;120:257–269. - PubMed
    1. Davis PJM, Wright EA. A new method for measuring cranial cavity volume and its application to the assessment of cerebral atrophy at autopsy. Neuropathology and applied neurobiology. 1977;3:341–358.
    1. Sgouros S, Goldin JH, Hockley AD, Wake MJ, Natarajan K. Intracranial volume change in childhood. Journal of neurosurgery. 1999;91:610–616. - PubMed
    1. Buckner RL, et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage. 2004;23:724–738. - PubMed
    1. Farias ST, et al. Maximal brain size remains an important predictor of cognition in old age, independent of current brain pathology. Neurobiology of aging. 2012;33:1758–1768. - PMC - PubMed

METHODS-ONLY REFERENCES

    1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. - PMC - PubMed
    1. Chauhan G, et al. Association of Alzheimer disease GWAS loci with MRI-markers of brain aging. Neurobiology of aging. 2015 - PMC - PubMed
    1. Finucane HK, et al. Partitioning heritability by functional category using GWAS summary statistics. 2015 - PMC - PubMed
    1. Roadmap Epigenomics C, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–330. - PMC - PubMed
    1. Horikoshi M, et al. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nature genetics. 2013;45:76–82. - PMC - PubMed

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