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Meta-Analysis
. 2017 Jan 18;8:13624.
doi: 10.1038/ncomms13624.

Novel Genetic Loci Associated With Hippocampal Volume

Derrek P Hibar  1 Hieab H H Adams  2   3 Neda Jahanshad  1 Ganesh Chauhan  4 Jason L Stein  1   5 Edith Hofer  6   7 Miguel E Renteria  8 Joshua C Bis  9 Alejandro Arias-Vasquez  10   11   12   13 M Kamran Ikram  2   14   15   16   17 Sylvane Desrivières  18 Meike W Vernooij  2   3 Lucija Abramovic  19 Saud Alhusaini  20   21 Najaf Amin  2 Micael Andersson  22 Konstantinos Arfanakis  23   24   25 Benjamin S Aribisala  26   27   28 Nicola J Armstrong  29   30 Lavinia Athanasiu  31   32 Tomas Axelsson  33 Ashley H Beecham  34   35 Alexa Beiser  36   37   38 Manon Bernard  39 Susan H Blanton  34   35 Marc M Bohlken  19 Marco P Boks  19 Janita Bralten  10   13 Adam M Brickman  40 Owen Carmichael  41 M Mallar Chakravarty  42   43 Qiang Chen  44 Christopher R K Ching  1   45 Vincent Chouraki  36   38   46 Gabriel Cuellar-Partida  8 Fabrice Crivello  47 Anouk Den Braber  48 Nhat Trung Doan  31 Stefan Ehrlich  49   50   51 Sudheer Giddaluru  52   53 Aaron L Goldman  44 Rebecca F Gottesman  54 Oliver Grimm  55 Michael E Griswold  56 Tulio Guadalupe  57   58 Boris A Gutman  1 Johanna Hass  59 Unn K Haukvik  31   60 David Hoehn  61 Avram J Holmes  50   62 Martine Hoogman  10   13 Deborah Janowitz  63 Tianye Jia  18 Kjetil N Jørgensen  31   60 Nazanin Karbalai  61 Dalia Kasperaviciute  64   65 Sungeun Kim  66   67   68 Marieke Klein  10   13 Bernd Kraemer  69 Phil H Lee  50   70   71   72   73 David C M Liewald  74 Lorna M Lopez  74 Michelle Luciano  74 Christine Macare  18 Andre F Marquand  13   75 Mar Matarin  64   76 Karen A Mather  29 Manuel Mattheisen  77   78   79 David R McKay  80   81 Yuri Milaneschi  82 Susana Muñoz Maniega  26   28   74 Kwangsik Nho  66   67   68 Allison C Nugent  83 Paul Nyquist  84 Loes M Olde Loohuis  85 Jaap Oosterlaan  86 Martina Papmeyer  87   88 Lukas Pirpamer  6 Benno Pütz  61 Adaikalavan Ramasamy  76   89   90 Jennifer S Richards  12   13   91 Shannon L Risacher  66   68 Roberto Roiz-Santiañez  92   93 Nanda Rommelse  11   13   91 Stefan Ropele  6 Emma J Rose  94 Natalie A Royle  26   28   74   95 Tatjana Rundek  96   97 Philipp G Sämann  61 Arvin Saremi  1 Claudia L Satizabal  36   38 Lianne Schmaal  98   99   100 Andrew J Schork  101   102 Li Shen  66   67   68 Jean Shin  39 Elena Shumskaya  10   13   75 Albert V Smith  103   104 Emma Sprooten  80   81   105 Lachlan T Strike  8   106 Alexander Teumer  107 Diana Tordesillas-Gutierrez  93   108 Roberto Toro  109 Daniah Trabzuni  76   110 Stella Trompet  111 Dhananjay Vaidya  112 Jeroen Van der Grond  113 Sven J Van der Lee  2 Dennis Van der Meer  114 Marjolein M J Van Donkelaar  10   13 Kristel R Van Eijk  115 Theo G M Van Erp  116 Daan Van Rooij  12   13   114 Esther Walton  49   117 Lars T Westlye  32   117 Christopher D Whelan  1   21 Beverly G Windham  118 Anderson M Winkler  80   119 Katharina Wittfeld  63   120 Girma Woldehawariat  83 Christiane Wolf  121 Thomas Wolfers  10   13 Lisa R Yanek  112 Jingyun Yang  24   122 Alex Zijdenbos  123 Marcel P Zwiers  13   75 Ingrid Agartz  31   60   124 Laura Almasy  125   126   127 David Ames  128   129 Philippe Amouyel  46 Ole A Andreassen  31   32 Sampath Arepalli  130 Amelia A Assareh  29 Sandra Barral  40 Mark E Bastin  26   28   74   95 Diane M Becker  112 James T Becker  131 David A Bennett  24   122 John Blangero  125 Hans van Bokhoven  10   13 Dorret I Boomsma  48 Henry Brodaty  29   132 Rachel M Brouwer  19 Han G Brunner  10   13   133 Randy L Buckner  50   134 Jan K Buitelaar  12   13   91 Kazima B Bulayeva  135 Wiepke Cahn  19 Vince D Calhoun  136   137 Dara M Cannon  83   138 Gianpiero L Cavalleri  21 Ching-Yu Cheng  14   15   139 Sven Cichon  140   141   142 Mark R Cookson  130 Aiden Corvin  94 Benedicto Crespo-Facorro  92   93 Joanne E Curran  125 Michael Czisch  61 Anders M Dale  143   144 Gareth E Davies  145 Anton J M De Craen  146 Eco J C De Geus  48 Philip L De Jager  71   147   148   149   150 Greig I De Zubicaray  151 Ian J Deary  74 Stéphanie Debette  4   36   152 Charles DeCarli  153 Norman Delanty  21   154 Chantal Depondt  155 Anita DeStefano  37   38 Allissa Dillman  130 Srdjan Djurovic  52   156 Gary Donohoe  157   158 Wayne C Drevets  83   159 Ravi Duggirala  125 Thomas D Dyer  125 Christian Enzinger  6 Susanne Erk  160 Thomas Espeseth  32   117 Iryna O Fedko  48 Guillén Fernández  12   13 Luigi Ferrucci  161 Simon E Fisher  13   57 Debra A Fleischman  24   162 Ian Ford  163 Myriam Fornage  164 Tatiana M Foroud  68   165 Peter T Fox  166 Clyde Francks  13   57 Masaki Fukunaga  167 J Raphael Gibbs  76   130 David C Glahn  80   81 Randy L Gollub  50   51   71 Harald H H Göring  125 Robert C Green  71   168 Oliver Gruber  69 Vilmundur Gudnason  103   104 Sebastian Guelfi  76 Asta K Håberg  169   170 Narelle K Hansell  8   106 John Hardy  76 Catharina A Hartman  114 Ryota Hashimoto  171   172 Katrin Hegenscheid  173 Andreas Heinz  160 Stephanie Le Hellard  52   53 Dena G Hernandez  76   130   174 Dirk J Heslenfeld  175 Beng-Choon Ho  176 Pieter J Hoekstra  114 Wolfgang Hoffmann  107   120 Albert Hofman  177 Florian Holsboer  61   178 Georg Homuth  177 Norbert Hosten  173 Jouke-Jan Hottenga  48 Matthew Huentelman  179 Hilleke E Hulshoff Pol  19 Masashi Ikeda  180 Clifford R Jack Jr  181 Mark Jenkinson  119 Robert Johnson  182 Erik G Jönsson  31   124 J Wouter Jukema  111 René S Kahn  19 Ryota Kanai  183   184   185 Iwona Kloszewska  186 David S Knopman  187 Peter Kochunov  188 John B Kwok  189   190 Stephen M Lawrie  87 Hervé Lemaître  191 Xinmin Liu  83   192 Dan L Longo  193 Oscar L Lopez  194 Simon Lovestone  195   196 Oliver Martinez  153 Jean-Luc Martinot  191 Venkata S Mattay  44   54   197 Colm McDonald  138 Andrew M McIntosh  74   87 Francis J McMahon  83 Katie L McMahon  198 Patrizia Mecocci  199 Ingrid Melle  31   32 Andreas Meyer-Lindenberg  55 Sebastian Mohnke  160 Grant W Montgomery  8 Derek W Morris  157 Thomas H Mosley  118 Thomas W Mühleisen  141   142 Bertram Müller-Myhsok  61   200   201 Michael A Nalls  130 Matthias Nauck  202   203 Thomas E Nichols  119   204 Wiro J Niessen  3   205   206 Markus M Nöthen  141   207 Lars Nyberg  22 Kazutaka Ohi  171 Rene L Olvera  166 Roel A Ophoff  19   85 Massimo Pandolfo  155 Tomas Paus  208   209   210 Zdenka Pausova  39   211 Brenda W J H Penninx  100 G Bruce Pike  212   213 Steven G Potkin  116 Bruce M Psaty  214 Simone Reppermund  29   215 Marcella Rietschel  55 Joshua L Roffman  50 Nina Romanczuk-Seiferth  160 Jerome I Rotter  216 Mina Ryten  76   89 Ralph L Sacco  35   96   97   217 Perminder S Sachdev  29   218 Andrew J Saykin  66   68   165 Reinhold Schmidt  6 Helena Schmidt  219 Peter R Schofield  189   190 Sigurdur Sigursson  103 Andrew Simmons  220   221   222 Andrew Singleton  130 Sanjay M Sisodiya  64 Colin Smith  223 Jordan W Smoller  50   70   71   72 Hilkka Soininen  224   225 Vidar M Steen  52   53 David J Stott  226 Jessika E Sussmann  87 Anbupalam Thalamuthu  29 Arthur W Toga  227 Bryan J Traynor  130 Juan Troncoso  228 Magda Tsolaki  229 Christophe Tzourio  4   230 Andre G Uitterlinden  2   231 Maria C Valdés Hernández  26   28   74   95 Marcel Van der Brug  232 Aad van der Lugt  3 Nic J A van der Wee  233 Neeltje E M Van Haren  19 Dennis van 't Ent  48 Marie-Jose Van Tol  234 Badri N Vardarajan  40 Bruno Vellas  235 Dick J Veltman  100 Henry Völzke  107 Henrik Walter  160 Joanna M Wardlaw  26   28   74   95 Thomas H Wassink  236 Michael E Weale  89 Daniel R Weinberger  44   237 Michael W Weiner  238 Wei Wen  29   218 Eric Westman  239 Tonya White  3   240 Tien Y Wong  14   15   139 Clinton B Wright  96   97   217 Ronald H Zielke  182 Alan B Zonderman  241 Nicholas G Martin  8 Cornelia M Van Duijn  2 Margaret J Wright  106   198 W T Longstreth  242 Gunter Schumann  18 Hans J Grabe  63 Barbara Franke  10   11   13 Lenore J Launer  243 Sarah E Medland  8 Sudha Seshadri  36   38 Paul M Thompson  1 M Arfan Ikram  2   3   244
Affiliations
Free PMC article
Meta-Analysis

Novel Genetic Loci Associated With Hippocampal Volume

Derrek P Hibar et al. Nat Commun. .
Free PMC article

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Figures

Figure 1
Figure 1. Common genetic variants associated with hippocampal volume (N=26,814 of European ancestry).
A Manhattan plot displays the association P value for each single-nucleotide polymorphism (SNP) in the genome (displayed as –log10 of the P-value). Genome-wide significance is shown for the P=5 × 10−8 threshold (solid line) and also for the suggestive significance threshold of P=1 × 10−6 (dotted line). The most significant SNP within an associated locus is labeled. For the significant loci and age-dependent loci (Chromosome 19) we labeled the nearest gene, which is not necessarily the gene of action.
Figure 2
Figure 2. Functional annotation within genome-wide significant loci.
For each panel (af), zoomed-in Manhattan plots (±400 kb from top SNP) are shown with gene models below (GENCODE version 19). Plots below are zoomed to highlight the genomic region that likely harbors the causal variant(s) (r2>0.8 from the top SNP). Genomic annotations from the Roadmap Epigenomics Consortium are displayed to indicate potential functionality (see Methods for detailed track information). Each plot was made using the LocusTrack software (see URLs).
Figure 3
Figure 3. Analysis of variance explained, functional annotation, and pathway analysis.
LDSCORE regression analysis for different functional annotation categories (described further in Finucane et al.26). Plotted values are the proportion of h2g explained divided by the proportion of SNPs in a given functional category. Values are significantly over- or under-represented if they differ significantly from 1. Values are plotted with a standard error calculated with a jackknife in LDSCORE. Evolutionarily conserved regions across mammals significantly contributed to the heritability of hippocampal volume (indicated by **).

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