Faculty Collaboration Database

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders. medRxiv 2023 Sep 02

Date

09/11/2023

Pubmed ID

37693460

Pubmed Central ID

PMC10491375

DOI

10.1101/2023.08.31.23294915

Abstract

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Author List

Nievergelt CM, Maihofer AX, Atkinson EG, Chen CY, Choi KW, Coleman JR, Daskalakis NP, Duncan LE, Polimanti R, Aaronson C, Amstadter AB, Andersen SB, Andreassen OA, Arbisi PA, Ashley-Koch AE, Austin SB, Avdibegoviç E, Babic D, Bacanu SA, Baker DG, Batzler A, Beckham JC, Belangero S, Benjet C, Bergner C, Bierer LM, Biernacka JM, Bierut LJ, Bisson JI, Boks MP, Bolger EA, Brandolino A, Breen G, Bressan RA, Bryant RA, Bustamante AC, Bybjerg-Grauholm J, Bækvad-Hansen M, Børglum AD, Børte S, Cahn L, Calabrese JR, Caldas-de-Almeida JM, Chatzinakos C, Cheema S, Clouston SAP, Colodro-Conde L, Coombes BJ, Cruz-Fuentes CS, Dale AM, Dalvie S, Davis LK, Deckert J, Delahanty DL, Dennis MF, deRoon-Cassini T, Desarnaud F, DiPietro CP, Disner SG, Docherty AR, Domschke K, Dyb G, Kulenovic AD, Edenberg HJ, Evans A, Fabbri C, Fani N, Farrer LA, Feder A, Feeny NC, Flory JD, Forbes D, Franz CE, Galea S, Garrett ME, Gelaye B, Gelernter J, Geuze E, Gillespie CF, Goci A, Goleva SB, Gordon SD, Grasser LR, Guindalini C, Haas M, Hagenaars S, Hauser MA, Heath AC, Hemmings SM, Hesselbrock V, Hickie IB, Hogan K, Hougaard DM, Huang H, Huckins LM, Hveem K, Jakovljevic M, Javanbakht A, Jenkins GD, Johnson J, Jones I, Jovanovic T, Karstoft KI, Kaufman ML, Kennedy JL, Kessler RC, Khan A, Kimbrel NA, King AP, Koen N, Kotov R, Kranzler HR, Krebs K, Kremen WS, Kuan PF, Lawford BR, Lebois LAM, Lehto K, Levey DF, Lewis C, Liberzon I, Linnstaedt SD, Logue MW, Lori A, Lu Y, Luft BJ, Lupton MK, Luykx JJ, Makotkine I, Maples-Keller JL, Marchese S, Marmar C, Martin NG, MartÍnez-Levy GA, McAloney K, McFarlane A, McLaughlin KA, McLean SA, Medland SE, Mehta D, Meyers J, Michopoulos V, Mikita EA, Milani L, Milberg W, Miller MW, Morey RA, Morris CP, Mors O, Mortensen PB, Mufford MS, Nelson EC, Nordentoft M, Norman SB, Nugent NR, O'Donnell M, Orcutt HK, Pan PM, Panizzon MS, Pathak GA, Peters ES, Peterson AL, Peverill M, Pietrzak RH, Polusny MA, Porjesz B, Powers A, Qin XJ, Ratanatharathorn A, Risbrough VB, Roberts AL, Rothbaum BO, Rothbaum AO, Roy-Byrne P, Ruggiero KJ, Rung A, Runz H, Rutten BPF, de Viteri SS, Salum GA, Sampson L, Sanchez SE, Santoro M, Seah C, Seedat S, Seng JS, Shabalin A, Sheerin CM, Silove D, Smith AK, Smoller JW, Sponheim SR, Stein DJ, Stensland S, Stevens JS, Sumner JA, Teicher MH, Thompson WK, Tiwari AK, Trapido E, Uddin M, Ursano RJ, Valdimarsdóttir U, van den Heuvel LL, Van Hooff M, van Rooij SJ, Vermetten E, Vinkers CH, Voisey J, Wang Z, Wang Y, Waszczuk M, Weber H, Wendt FR, Werge T, Williams MA, Williamson DE, Winsvold BS, Winternitz S, Wolf EJ, Wolf C, Xia Y, Xiong Y, Yehuda R, Young RM, Young KA, Zai CC, Zai GC, Zervas M, Zhao H, Zoellner LA, Zwart JA, Stein MB, Ressler KJ, Koenen KC

Authors

Carisa Bergner Biostatistician II in the Surgery department at Medical College of Wisconsin
Amber Brandolino in the CTSI department at Medical College of Wisconsin - CTSI
Terri A. deRoon Cassini PhD Center Director, Professor in the Surgery department at Medical College of Wisconsin