Journal Article

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Domschke, Katharina, Daskalakis, Nikolaos P., Tiwari, Arun K., Khan, Alaptagin, Nievergelt, Caroline M., Mors, Ole, Norman, Sonya B., Bybjerg-Grauholm, Jonas, Boks, Marco P., Hogan, Kelleigh, Smoller, Jordan W., Huckins, Laura M., Polimanti, Renato, Stein, Dan J., Dalvie, Shareefa, Hveem, Kristian, Javanbakht, Arash, Xiong, Ying, Davis, Lea K., Marmar, Charles, Risbrough, Victoria B., Mufford, Mary S., Batzler, Anthony, McLean, Samuel A., Gordon, Scott D., van den Heuvel, Leigh L., Amstadter, Ananda B., Wolf, Erika J., Maihofer, Adam X., Martin, Nicholas G., Martínez-Levy, Gabriela A., Hauser, Michael A., Makotkine, Iouri, Miller, Mark W., Jenkins, Gregory D., Kennedy, James L., Trapido, Edward, Gillespie, Charles F., Lori, Adriana, Valdimarsdóttir, Unnur, Bustamante, Angela C., Santoro, Marcos, Van Hooff, Miranda, Jovanovic, Tanja, Nelson, Elliot C., Kotov, Roman, Morey, Rajendra A., Kulenović, Alma Džubur, Vermetten, Eric, Hougaard, David Michael, Linnstaedt, Sarah D., Peverill, Matthew, Morris, Charles Phillip, Bisson, Jonathan I., de Viteri, Stacey Saenz, Zai, Gwyneth C., van Rooij, Sanne J.

2024

Overview

Post-traumatic 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 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1 , GRM8 and CACNA1E ), developmental, axon guidance and transcription factors (for example, FOXP2 , EFNA5 and DCC ), synaptic structure and function genes (for example, PCLO , NCAM1 and PDE4B ) and endocrine or immune regulators (for example, ESR1 , TRAF3 and 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. Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 692/699/476 / Agriculture / American Indian or Alaska Native / Animal Genetics and Genomics / Axon guidance / Biomedical and Life Sciences / Biomedicine / Black or African American / Brain research / Cancer Research / Comorbidity / Data collection / Electronic health records / Gene Function / Genes / Genetic Loci / Genetic Predisposition to Disease / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Human Genetics / Humans / Ion channels / Mental disorders / Meta-analysis / Minority & ethnic groups / Modulators / Neurobiology / Neuromodulation / Neurosciences / Pathophysiology / Polymorphism, Single Nucleotide / Post traumatic stress disorder / Psychological stress / Stress Disorders, Post-Traumatic - genetics / Structure-function relationships / Transcription factors / White / White People - genetics / X chromosomes