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Meta-Analysis
. 2022 Apr 1;91(7):626-636.
doi: 10.1016/j.biopsych.2021.09.020. Epub 2021 Sep 28.

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Adam X Maihofer  1 , Karmel W Choi  2 , Jonathan R I Coleman  3 , Nikolaos P Daskalakis  4 , Christy A Denckla  5 , Elizabeth Ketema  6 , Rajendra A Morey  7 , Renato Polimanti  8 , Andrew Ratanatharathorn  9 , Katy Torres  6 , Aliza P Wingo  10 , Clement C Zai  11 , Allison E Aiello  12 , Lynn M Almli  13 , Ananda B Amstadter  14 , Soren B Andersen  15 , Ole A Andreassen  16 , Paul A Arbisi  17 , Allison E Ashley-Koch  7 , S Bryn Austin  18 , Esmina Avdibegović  19 , Anders D Borglum  20 , Dragan Babić  21 , Marie Bækvad-Hansen  22 , Dewleen G Baker  23 , Jean C Beckham  24 , Laura J Bierut  25 , Jonathan I Bisson  26 , Marco P Boks  27 , Elizabeth A Bolger  28 , Bekh Bradley  29 , Meghan Brashear  30 , Gerome Breen  3 , Richard A Bryant  31 , Angela C Bustamante  32 , Jonas Bybjerg-Grauholm  22 , Joseph R Calabrese  33 , José M Caldas-de-Almeida  34 , Chia-Yen Chen  35 , Anders M Dale  36 , Shareefa Dalvie  37 , Jürgen Deckert  38 , Douglas L Delahanty  39 , Michelle F Dennis  24 , Seth G Disner  40 , Katharina Domschke  41 , Laramie E Duncan  42 , Alma Džubur Kulenović  43 , Christopher R Erbes  17 , Alexandra Evans  26 , Lindsay A Farrer  44 , Norah C Feeny  45 , Janine D Flory  46 , David Forbes  47 , Carol E Franz  48 , Sandro Galea  49 , Melanie E Garrett  7 , Aarti Gautam  50 , Bizu Gelaye  51 , Joel Gelernter  52 , Elbert Geuze  53 , Charles F Gillespie  13 , Aferdita Goçi  54 , Scott D Gordon  55 , Guia Guffanti  28 , Rasha Hammamieh  50 , Michael A Hauser  56 , Andrew C Heath  57 , Sian M J Hemmings  58 , David Michael Hougaard  22 , Miro Jakovljević  59 , Marti Jett  60 , Eric Otto Johnson  61 , Ian Jones  26 , Tanja Jovanovic  12 , Xue-Jun Qin  7 , Karen-Inge Karstoft  62 , Milissa L Kaufman  28 , Ronald C Kessler  63 , Alaptagin Khan  28 , Nathan A Kimbrel  64 , Anthony P King  65 , Nastassja Koen  66 , Henry R Kranzler  67 , William S Kremen  68 , Bruce R Lawford  69 , Lauren A M Lebois  28 , Catrin Lewis  26 , Israel Liberzon  70 , Sarah D Linnstaedt  71 , Mark W Logue  72 , Adriana Lori  73 , Božo Lugonja  26 , Jurjen J Luykx  74 , Michael J Lyons  75 , Jessica L Maples-Keller  13 , Charles Marmar  76 , Nicholas G Martin  55 , Douglas Maurer  77 , Matig R Mavissakalian  33 , Alexander McFarlane  78 , Regina E McGlinchey  79 , Katie A McLaughlin  80 , Samuel A McLean  81 , Divya Mehta  82 , Rebecca Mellor  83 , Vasiliki Michopoulos  13 , William Milberg  79 , Mark W Miller  84 , Charles Phillip Morris  85 , Ole Mors  86 , Preben B Mortensen  87 , Elliot C Nelson  25 , Merete Nordentoft  88 , Sonya B Norman  89 , Meaghan O'Donnell  90 , Holly K Orcutt  91 , Matthew S Panizzon  48 , Edward S Peters  30 , Alan L Peterson  92 , Matthew Peverill  93 , Robert H Pietrzak  94 , Melissa A Polusny  17 , John P Rice  25 , Victoria B Risbrough  6 , Andrea L Roberts  95 , Alex O Rothbaum  45 , Barbara O Rothbaum  13 , Peter Roy-Byrne  96 , Kenneth J Ruggiero  97 , Ariane Rung  30 , Bart P F Rutten  98 , Nancy L Saccone  25 , Sixto E Sanchez  99 , Dick Schijven  74 , Soraya Seedat  58 , Antonia V Seligowski  28 , Julia S Seng  100 , Christina M Sheerin  14 , Derrick Silove  101 , Alicia K Smith  102 , Jordan W Smoller  103 , Scott R Sponheim  17 , Dan J Stein  66 , Jennifer S Stevens  13 , Martin H Teicher  104 , Wesley K Thompson  105 , Edward Trapido  30 , Monica Uddin  106 , Robert J Ursano  107 , Leigh Luella van den Heuvel  58 , Miranda Van Hooff  78 , Eric Vermetten  108 , Christiaan H Vinkers  109 , Joanne Voisey  82 , Yunpeng Wang  110 , Zhewu Wang  111 , Thomas Werge  112 , Michelle A Williams  51 , Douglas E Williamson  113 , Sherry Winternitz  28 , Christiane Wolf  38 , Erika J Wolf  84 , Rachel Yehuda  114 , Keith A Young  115 , Ross McD Young  116 , Hongyu Zhao  117 , Lori A Zoellner  96 , Magali Haas  118 , Heather Lasseter  118 , Allison C Provost  118 , Rany M Salem  119 , Jonathan Sebat  120 , Richard A Shaffer  121 , Tianying Wu  122 , Stephan Ripke  123 , Mark J Daly  124 , Kerry J Ressler  125 , Karestan C Koenen  126 , Murray B Stein  127 , Caroline M Nievergelt  6
Affiliations
Meta-Analysis

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Adam X Maihofer et al. Biol Psychiatry. .

Erratum in

  • Erratum.
    [No authors listed] [No authors listed] Biol Psychiatry. 2022 Apr 1;91(7):690. doi: 10.1016/j.biopsych.2022.02.001. Biol Psychiatry. 2022. PMID: 35272769 No abstract available.

Abstract

Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).

Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.

Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.

Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Keywords: GWAS; Genetics; Heritability; PTSD; PheWAS; Trauma.

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Figures

Figure 1.
Figure 1.
Manhattan plots of genome-wide association study (GWAS) associations. The x-axis is the position on the genome, ordered by chromosome and base-pair position. The y-axis is the −log10 p value of association. Each dot represents the association between a given single nucleotide polymorphism and the trait. Colors alternate between chromosomes, with odd chromosomes colored blue and even chromosomes colored teal. (A) Results of posttraumatic stress disorder GWASs. (B) Results of lifetime trauma exposure GWASs. (C) Posttraumatic stress disorder–specific results of MTAG (Multi-Trait Analysis of GWAS) analysis of posttraumatic stress disorder and lifetime trauma exposure.
Figure 2.
Figure 2.
Comparison of the genetic correlations of posttraumatic stress disorder (PTSD) and lifetime trauma exposure (LTE) with other traits. The x-axis is the genetic correlation between LTE and a given trait from the LD Hub. The y-axis is the genetic correlation between PTSD and a given trait. Each dot depicts a given trait. Colored (black, red, or blue) dots indicate traits with significant genetic correlation to both PTSD and LTE after Bonferroni adjustment. Noncolored (gray) dots indicate traits where genetic correlation is not significant after Bonferroni adjustment. Blue dots indicate traits with significantly higher genetic correlation with PTSD than with LTE. Red dots indicate traits with significantly higher correlation with LTE than with PTSD. The top 5 traits with a significantly higher correlation to PTSD than LTE and top trait with significantly higher correlation to LTE than PTSD have been labeled.
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Comment in

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