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The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration.

ABSTRACT: The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10?000 cases and 30?000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration-of a scope that is unprecedented in the field of traumatic stress-will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.

SUBMITTER: Logue MW

PROVIDER: S-EPMC4538342 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration.

Logue Mark W MW Amstadter Ananda B AB Baker Dewleen G DG Duncan Laramie L Koenen Karestan C KC Liberzon Israel I Miller Mark W MW Morey Rajendra A RA Nievergelt Caroline M CM Ressler Kerry J KJ Smith Alicia K AK Smoller Jordan W JW Stein Murray B MB Sumner Jennifer A JA Uddin Monica M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150423 10

The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for th ...[more]

PMID: 25904361

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Project description:Genetic susceptibility factors behind psychiatric disorders typically contribute small effects individually. A possible explanation for the missing heritability is that the effects of common variants are not only polygenic but also non-additive, appearing only when interactions within large groups are taken into account. Here, we tested this hypothesis for schizophrenia (SZ) and bipolar disorder (BP) disease risks, and identified genetic factors shared with posttraumatic stress disorder (PTSD). When considered independently, few single-nucleotide polymorphisms (SNPs) reached genome-wide significance. In contrast, when SNPs were selected in groups (containing up to thousands each) and the collective effects of all interactions were estimated, the association strength for SZ/BP rose dramatically with a combined sample size of 7187 cases and 8309 controls. We identified a large number of genes and pathways whose association was significant only when interaction effects were included. The gene with highest association was CSMD1, which encodes a negative regulator of complement activation. Pathways for glycosaminoglycan (GAG) synthesis exhibited strong association in multiple contexts. Taken together, highly associated pathways suggested a pathogenesis mechanism where maternal immune activation causes disruption of neurogenesis (compounded by impaired cell cycle, DNA repair and neuronal migration) and deficits in cortical interneurons, leading to symptoms triggered by synaptic pruning. Increased risks arise from GAG deficiencies causing complement activation and excessive microglial action. Analysis of PTSD data sets suggested an etiology common to SZ/BP: interneuron deficiency can also lead to impaired control of fear responses triggered by trauma. We additionally found PTSD risk factors affecting synaptic plasticity and fatty acid signaling, consistent with the fear extinction model. Our results suggest that much of the missing heritability of psychiatric disorders resides in non-additive interaction effects.

Dataset Information

The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration.

Publications

The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration.

Similar Datasets

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