Advertisement

Genomic Approaches to Posttraumatic Stress Disorder: The Psychiatric Genomic Consortium Initiative

Published:February 03, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.01.020

      Abstract

      Posttraumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (single nucleotide polymorphism–based heritability) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, fewer than 10 large-scale genome-wide association studies of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group has brought together more than 200 scientists with the goal to increase sample size for genome-wide association studies and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes more than 32,000 PTSD cases and 100,000 trauma-exposed control subjects, and collection is ongoing. The first results found a significant shared genetic risk of PTSD with other psychiatric disorders and sex-biased heritability estimates with higher heritability in female individuals compared with male individuals. This review describes the scope and current focus of the Psychiatric Genomics Consortium PTSD group and its expansion from the initial genome-wide association study group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of “omics”-based studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Psychiatric Association
        Trauma- and Stressor-Related Disorders: Diagnostic and Statistical Manual of Mental Disorders, 5th ed.
        American Psychiatric Association, Washington, DC2013
        • Yehuda R.
        • Hoge C.W.
        • McFarlane A.C.
        • Vermetten E.
        • Lanius R.A.
        • Nievergelt C.M.
        • et al.
        Post-traumatic stress disorder.
        Nat Rev Dis Primers. 2015; 1: 15057
        • Kessler R.C.
        • Sonnega A.
        • Bromet E.
        • Hughes M.
        • Nelson C.B.
        Posttraumatic stress disorder in the National Comorbidity Survey.
        Arch Gen Psychiatry. 1995; 52: 1048-1060
        • True W.J.
        • Rice J.
        • Eisen S.A.
        • Heath A.C.
        • Goldberg J.
        • Lyons M.J.
        • et al.
        A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms.
        Arch Gen Psychiatry. 1993; 50: 257-264
        • Stein M.B.
        • Jang K.J.
        • Taylor S.
        • Vernon P.A.
        • Livesley W.J.
        Genetic and environmental influences on trauma exposure and posttraumatic stress disorder: A twin study.
        Am J Psychiatry. 2002; 159: 1675-1681
        • Sartor C.E.
        • Grant J.D.
        • Lynskey M.T.
        • McCutcheon V.V.
        • Waldron M.
        • Statham D.J.
        • et al.
        Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression.
        Arch Gen Psychiatry. 2012; 69: 293-299
        • Sartor C.E.
        • McCutcheon V.V.
        • Pommer N.E.
        • Nelson E.C.
        • Grant J.D.
        • Duncan A.E.
        • et al.
        Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women.
        Psychol Med. 2011; 41: 1497-1505
        • Ioannidis J.P.
        • Tarone R.
        • McLaughlin J.K.
        The false-positive to false-negative ratio in epidemiologic studies.
        Epidemiology. 2011; 22: 450-456
        • Sullivan P.F.
        • Agrawal A.
        • Bulik C.M.
        • Andreassen O.A.
        • Borglum A.D.
        • Breen G.
        • et al.
        Psychiatric genomics: An update and an agenda.
        Am J Psychiatry. 2018; 175: 15-27
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Sklar P.
        • Ripke S.
        • Scott L.J.
        • Andreassen O.A.
        • Cichon S.
        • Craddock N.
        • et al.
        Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
        Nat Genet. 2011; 43: 977-983
        • Hyde C.L.
        • Nagle M.W.
        • Tian C.
        • Chen X.
        • Paciga S.A.
        • Wendland J.R.
        • et al.
        Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.
        Nat Genet. 2016; 48: 1031-1036
        • Guffanti G.
        • Galea S.
        • Yan L.
        • Roberts A.L.
        • Solovieff N.
        • Aiello A.E.
        • et al.
        Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women.
        Psychoneuroendocrinology. 2013; 38: 3029-3038
        • Logue M.W.
        • Baldwin C.
        • Guffanti G.
        • Melista E.
        • Wolf E.J.
        • Reardon A.F.
        • et al.
        A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus.
        Mol Psychiatry. 2013; 18: 937-942
        • Xie P.
        • Kranzler H.R.
        • Yang C.
        • Zhao H.
        • Farrer L.A.
        • Gelernter J.
        Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder.
        Biol Psychiatry. 2013; 74: 656-663
        • Nievergelt C.M.
        • Maihofer A.X.
        • Mustapic M.
        • Yurgil K.A.
        • Schork N.J.
        • Miller M.W.
        • et al.
        Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene.
        Psychoneuroendocrinology. 2015; 51: 459-471
        • Logue M.W.
        • Amstadter A.B.
        • Baker D.G.
        • Duncan L.
        • Koenen K.C.
        • Liberzon I.
        • et al.
        The Psychiatric Genomics Consortium Posttraumatic Stress Disorder workgroup: Posttraumatic stress disorder enters the age of large-scale genomic collaboration.
        Neuropsychopharmacology. 2015; 40: 2287-2297
        • Solovieff N.
        • Roberts A.L.
        • Ratanatharathorn A.
        • Haloosim M.
        • De Vivo I.
        • King A.P.
        • et al.
        Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples.
        Neuropsychopharmacology. 2014; 39: 1872-1879
        • Almli L.M.
        • Srivastava A.
        • Fani N.
        • Kerley K.
        • Mercer K.B.
        • Feng H.
        • et al.
        Follow-up and extension of a prior genome-wide association study of posttraumatic stress disorder: Gene × Environment associations and structural magnetic resonance imaging in a highly traumatized African-American civilian population.
        Biol Psychiatry. 2014; 76: e3-e4
        • Stein M.B.
        • Chen C.Y.
        • Ursano R.J.
        • Cai T.
        • Gelernter J.
        • Heeringa S.G.
        • et al.
        Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US Army soldiers.
        JAMA Psychiatry. 2016; 73: 695-704
        • Ashley-Koch A.E.
        • Garrett M.E.
        • Gibson J.
        • Liu Y.
        • Dennis M.F.
        • Kimbrel N.A.
        • et al.
        Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq–Afghanistan era veterans.
        J Affect Disord. 2015; 184: 225-234
        • Cross-Disorder Group of the Psychiatric Genomics Consortium
        Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.
        Lancet. 2013; 381: 1371-1379
        • Armour C.
        • Mullerova J.
        • Elhai J.D.
        A systematic literature review of PTSD's latent structure in the Diagnostic and Statistical Manual of Mental Disorders: DSM-IV to DSM-5.
        Clin Psychol Rev. 2016; 44: 60-74
        • Duncan L.E.
        • Ratanatharathorn A.
        • Aiello A.E.
        • Almli L.M.
        • Amstadter A.B.
        • Ashley-Koch A.E.
        • et al.
        Largest GWAS of PTSD (N = 20 070) yields genetic overlap with schizophrenia and sex differences in heritability.
        Mol Psychiatry. 2018; 23: 666-673
        • Zhou X.
        • Stephens M.
        Efficient multivariate linear mixed model algorithms for genome-wide association studies.
        Nat Methods. 2014; 11: 407-409
        • Gratten J.
        • Wray N.R.
        • Keller M.C.
        • Visscher P.M.
        Large-scale genomics unveils the genetic architecture of psychiatric disorders.
        Nat Neurosci. 2014; 17: 782-790
        • Otowa T.
        • Hek K.
        • Lee M.
        • Byrne E.M.
        • Mirza S.S.
        • Nivard M.G.
        • et al.
        Meta-analysis of genome-wide association studies of anxiety disorders.
        Mol Psychiatry. 2016; 21: 1391-1399
        • Sumner J.A.
        • Duncan L.E.
        • Wolf E.J.
        • Amstadter A.B.
        • Baker D.G.
        • Beckham J.C.
        • et al.
        Letter to the Editor: Posttraumatic stress disorder has genetic overlap with cardiometabolic traits.
        Psychol Med. 2017; 47: 2036-2039
        • Michopoulos V.
        • Vester A.
        • Neigh G.
        Posttraumatic stress disorder: A metabolic disorder in disguise?.
        Exp Neurol. 2016; 284: 220-229
        • Passos I.C.
        • Vasconcelos-Moreno M.P.
        • Costa L.G.
        • Kunz M.
        • Brietzke E.
        • Quevedo J.
        • et al.
        Inflammatory markers in post-traumatic stress disorder: A systematic review, meta-analysis, and meta-regression.
        Lancet Psychiatry. 2015; 2: 1002-1012
        • Mehta D.
        • Binder E.B.
        Gene × Environment vulnerability factors for PTSD: The HPA-axis.
        Neuropharmacology. 2012; 62: 654-662
        • Andrews J.A.
        • Neises K.D.
        Cells, biomarkers, and post-traumatic stress disorder: Evidence for peripheral involvement in a central disease.
        J Neurochem. 2012; 120: 26-36
        • Zieker J.
        • Zieker D.
        • Jatzko A.
        • Dietzsch J.
        • Nieselt K.
        • Schmitt A.
        • et al.
        Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder.
        Mol Psychiatry. 2007; 12: 116-118
        • Segman R.
        • Shefi N.
        • Goltser-Dubner T.
        • Friedman N.
        • Kaminski N.
        • Shalev A.
        Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors.
        Mol Psychiatry. 2005; 10: 500-513
        • Sarapas C.
        • Cai G.
        • Bierer L.M.
        • Golier J.A.
        • Galea S.
        • Ising M.
        • et al.
        Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks.
        Dis Markers. 2011; 30: 101-110
        • Yehuda R.
        • Cai G.
        • Golier J.A.
        • Sarapas C.
        • Galea S.
        • Ising M.
        • et al.
        Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.
        Biol Psychiatry. 2009; 66: 708-711
        • O’Donovan A.
        • Sun B.
        • Cole S.
        • Rempel H.
        • Lenoci M.
        • Pulliam L.
        • et al.
        Transcriptional control of monocyte gene expression in post-traumatic stress disorder.
        Dis Markers. 2011; 30: 123-132
        • Neylan T.C.
        • Sun B.
        • Rempel H.
        • Ross J.
        • Lenoci M.
        • O'Donovan A.
        • et al.
        Suppressed monocyte gene expression profile in men versus women with PTSD.
        Brain Behav Immun. 2011; 25: 524-531
        • Logue M.W.
        • Smith A.K.
        • Baldwin C.
        • Wolf E.J.
        • Guffanti G.
        • Ratanatharathorn A.
        • et al.
        An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress.
        Psychoneuroendocrinology. 2015; 57: 1-13
        • Mehta D.
        • Klengel T.
        • Conneely K.N.
        • Smith A.K.
        • Altmann A.
        • Pace T.W.
        • et al.
        Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.
        Proc Natl Acad Sci U S A. 2013; 110: 8302-8307
        • Wingo A.P.
        • Almli L.M.
        • Stevens J.J.
        • Klengel T.
        • Uddin M.
        • Li Y.
        • et al.
        DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression.
        Nat Commun. 2015; 6 ([(2016): Corrigendum, Nat Commun 7:10958.]): 10106
        • Breen M.S.
        • Maihofer A.X.
        • Glatt S.J.
        • Tylee D.S.
        • Chandler S.D.
        • Tsuang M.T.
        • et al.
        Gene networks specific for innate immunity define post-traumatic stress disorder.
        Mol Psychiatry. 2015; 20: 1538-1545
        • Breen M.S.
        • Tylee D.S.
        • Maihofer A.X.
        • Neylan T.C.
        • Mehta D.
        • Binder E.
        • et al.
        PTSD blood transcriptome mega-analysis: Shared inflammatory pathways across biological sex and modes of trauma.
        Neuropsychopharmacology. 2018; 43: 469-481
        • Smith A.K.
        • Conneely K.N.
        • Kilaru V.
        • Mercer K.B.
        • Weiss T.E.
        • Bradley B.
        • et al.
        Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.
        Am J Med Genet B Neuropsychiatr Genet. 2011; 156: 700-708
        • Ressler K.J.
        • Mercer K.B.
        • Bradley B.
        • Jovanovic T.
        • Mahan A.
        • Kerley K.
        • et al.
        Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
        Nature. 2011; 470: 492-497
        • Uddin M.
        • Aiello A.E.
        • Wildman D.E.
        • Koenen K.C.
        • Pawelec G.
        • de Los Santos R.
        • et al.
        Epigenetic and immune function profiles associated with posttraumatic stress disorder.
        Proc Natl Acad Sci U S A. 2010; 107: 9470-9475
        • Mehta D.
        • Bruenig D.
        • Carrillo-Roa T.
        • Lawford B.
        • Harvey W.
        • Morris C.P.
        • et al.
        Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD.
        Acta Psychiatr Scand. 2017; 136: 493-505
        • Hammamieh R.
        • Chakraborty N.
        • Gautam A.
        • Muhie S.
        • Yang R.
        • Donohue D.
        • et al.
        Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans.
        Transl Psychiatry. 2017; 7e1169
        • Kuan P.F.
        • Waszczuk M.A.
        • Kotov R.
        • Marsit C.J.
        • Guffanti G.
        • Gonzalez A.
        • et al.
        An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders.
        Transl Psychiatry. 2017; 7e1158
        • Rutten B.P.F.
        • Vermetten E.
        • Vinkers C.H.
        • Ursini G.
        • Daskalakis N.P.
        • Pishva E.
        • et al.
        Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder.
        Mol Psychiatry. 2017; ([published online ahead of print Jun 20])
        • Bam M.
        • Yang X.
        • Zumbrun E.E.
        • Zhong Y.
        • Zhou J.
        • Ginsberg J.P.
        • et al.
        Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation.
        Sci Rep. 2016; 6: 31209
        • Raison C.L.
        • Capuron L.
        • Miller A.H.
        Cytokines sing the blues: Inflammation and the pathogenesis of depression.
        Trends Immunol. 2006; 27: 24-31
        • Maddox S.A.
        • Kilaru V.
        • Shin J.
        • Jovanovic T.
        • Almli L.M.
        • Dias B.G.
        • et al.
        Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD.
        Mol Psychiatry. 2018; 23: 658-665
        • Admon R.
        • Milad M.R.
        • Hendler T.
        A causal model of post-traumatic stress disorder: Disentangling predisposed from acquired neural abnormalities.
        Trends Cogn Sci. 2013; 17: 337-347
        • Horvath S.
        DNA methylation age of human tissues and cell types.
        Genome Biol. 2013; 14: R115
        • Zannas A.S.
        • Arloth J.
        • Carrillo-Roa T.
        • Iurato S.
        • Röh S.
        • Ressler K.J.
        • et al.
        Lifetime stress accelerates epigenetic aging in an urban, African American cohort: Relevance of glucocorticoid signaling.
        Genome Biol. 2015; 16: 266
        • Marioni R.E.
        • Shah S.
        • McRae A.F.
        • Chen B.H.
        • Colicino E.
        • Harris S.E.
        • et al.
        DNA methylation age of blood predicts all-cause mortality in later life.
        Genome Biol. 2015; 16: 25
        • Klengel T.
        • Mehta D.
        • Anacker C.
        • Rex-Haffner M.
        • Pruessner J.C.
        • Pariante C.M.
        • et al.
        Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions.
        Nat Neurosci. 2013; 16: 33-41
        • Wolf E.J.
        • Logue M.W.
        • Hayes J.P.
        • Sadeh N.
        • Schichman S.A.
        • Stone A.
        • et al.
        Accelerated DNA methylation age: Associations with PTSD and neural integrity.
        Psychoneuroendocrinology. 2016; 63: 155-162
        • Ratanatharathorn A.
        • Boks M.P.
        • Maihofer A.X.
        • Aiello A.E.
        • Amstadter A.B.
        • Ashley-Koch A.E.
        • et al.
        Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline.
        Am J Med Genet B Neuropsychiatr Genet. 2017; 174: 619-630
        • Geschwind D.H.
        • Flint J.
        Genetics and genomics of psychiatric disease.
        Science. 2015; 349: 1489-1494
        • Potkin S.
        • Guffanti G.
        • Lakatos A.
        • Turner J.
        • Kruggel F.
        • Fallon J.
        • et al.
        Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease.
        PLoS One. 2009; 4e6501
        • Gottesman II,
        • Gould T.D.
        The endophenotype concept in psychiatry: Etymology and strategic intentions.
        Am J Psychiatry. 2003; 160: 636-645
        • Flint J.
        • Timpson N.
        • Munafò M.
        Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease.
        Trends Neurosci. 2014; 37: 733-741
        • Thompson P.M.
        • Andreassen O.A.
        • Arias-Vasquez A.
        • Bearden C.E.
        • Boedhoe P.S.
        • Brouwer R.M.
        • et al.
        ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide.
        NeuroImage. 2017; 145: 389-408
        • Logue M.W.
        • van Rooij S.J.H.
        • Dennis E.L.
        • Davis S.L.
        • Hayes J.P.
        • Stevens J.S.
        • et al.
        Smaller hippocampal volume in posttraumatic stress disorder: A multisite ENIGMA-PGC study: Subcortical volumetry results from posttraumatic stress disorder consortia.
        Biol Psychiatry. 2018; 83: 244-253
        • Bremner J.D.
        • Randall P.
        • Scott T.M.
        • Bronen R.A.
        • Seibyl J.P.
        • Southwick S.M.
        • et al.
        MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder.
        Am J Psychiatry. 1995; 152: 973-981
        • Hibar D.P.
        • Stein J.L.
        • Renteria M.E.
        • Arias-Vasquez A.
        • Desrivieres S.
        • Jahanshad N.
        • et al.
        Common genetic variants influence human subcortical brain structures.
        Nature. 2015; 520: 224-229
        • Hayes J.P.
        • Logue M.W.
        • Sadeh N.
        • Spielberg J.M.
        • Verfaellie M.
        • Hayes S.M.
        • et al.
        Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer’s disease.
        Brain. 2017; 140: 813-825
        • Vukojevic V.
        • Kolassa I.T.
        • Fastenrath M.
        • Gschwind L.
        • Spalek K.
        • Milnik A.
        • et al.
        Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.
        J Neurosci. 2014; 34: 10274-10284
        • Sadeh N.
        • Spielberg J.M.
        • Logue M.W.
        • Wolf E.J.
        • Smith A.K.
        • Lusk J.
        • et al.
        SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.
        Mol Psychiatry. 2016; 21: 357-363
        • Zhu L.
        • Bhattacharyya A.
        • Kurali E.
        • Anderson A.
        • Menius A.
        • Lee K.
        Review of integrative analysis challenges in systems biology.
        Stat Biopharm Res. 2011; 3: 561-568
        • Chang L.C.
        • Lin H.M.
        • Sibille E.
        • Tseng G.C.
        Meta-analysis methods for combining multiple expression profiles: Comparisons, statistical characterization and an application guideline.
        BMC Bioinformatics. 2013; 14: 368
        • Kim J.
        • Patel K.
        • Jung H.
        • Kuo W.P.
        • Ohno-Machado L.
        AnyExpress: Integrated toolkit for analysis of cross-platform gene expression data using a fast interval matching algorithm.
        BMC Bioinformatics. 2011; 12: 75
        • Campain A.
        • Yang Y.H.
        Comparison study of microarray meta-analysis methods.
        BMC Bioinformatics. 2010; 11: 408
        • Ramasamy A.
        • Mondry A.
        • Holmes C.C.
        • Altman D.G.
        Key issues in conducting a meta-analysis of gene expression microarray datasets.
        PLoS Med. 2008; 5e184
        • Chrétien S.
        • Guyeux C.
        • Conesa B.
        • Delage-Mouroux R.
        • Jouvenot M.
        • Huetz P.
        • et al.
        A Bregman-proximal point algorithm for robust non-negative matrix factorization with possible missing values and outliers—Application to gene expression analysis.
        BMC Bioinformatics. 2016; 17: 284
        • Wang J.
        • Gamazon E.R.
        • Pierce B.L.
        • Stranger B.E.
        • Im H.K.
        • Gibbons R.D.
        • et al.
        Imputing gene expression in uncollected tissues within and beyond GTEx.
        Am J Hum Genet. 2016; 98: 697-708
        • Yang Y.
        • Xu Z.
        • Song D.
        Missing value imputation for microRNA expression data by using a GO-based similarity measure.
        BMC Bioinformatics. 2016; 17: 10
        • Li H.
        • Zhao C.
        • Shao F.
        • Li G.Z.
        • Wang X.
        A hybrid imputation approach for microarray missing value estimation.
        BMC Genomics. 2015; 16: S1
        • Liew A.W.
        • Law N.F.
        • Yan H.
        Missing value imputation for gene expression data: Computational techniques to recover missing data from available information.
        Brief Bioinform. 2011; 12: 498-513
        • Noureddine M.A.
        • Li Y.J.
        • van der Walt J.M.
        • Walters R.
        • Jewett R.M.
        • Xu H.
        • et al.
        Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.
        Mov Disord. 2005; 20: 1299-1309
        • Bharadwaj R.A.
        • Jaffe A.E.
        • Chen Q.
        • Deep-Soboslay A.
        • Goldman A.L.
        • Mighdoll M.I.
        • et al.
        Genetic risk mechanisms of posttraumatic stress disorder in the human brain.
        J Neurosci Res. 2018; 96: 21-30
        • Almli L.M.
        • Stevens J.S.
        • Smith A.K.
        • Kilaru V.
        • Meng Q.
        • Flory J.
        • et al.
        A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces.
        Am J Med Genet B Neuropsychiatr Genet. 2015; 168: 327-336
        • Pasaniuc B.
        • Price A.L.
        Dissecting the genetics of complex traits using summary association statistics.
        Nat Rev Genet. 2017; 18: 117-127
        • Mustapic M.
        • Maihofer A.X.
        • Mahata M.
        • Chen Y.
        • Baker D.G.
        • O’Connor D.T.
        • et al.
        The catecholamine biosynthetic enzyme dopamine beta-hydroxylase (DBH): First genome-wide search positions trait-determining variants acting additively in the proximal promoter.
        Hum Mol Genet. 2014; 23: 6375-6384
        • Polimanti R.
        • Amstadter A.B.
        • Stein M.B.
        • Almli L.M.
        • Baker D.G.
        • Bierut L.J.
        • et al.
        A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder.
        Genome Med. 2017; 9: 99
        • Consortium G
        The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans.
        Science. 2015; 348: 648-660
        • Akbarian S.
        • Liu C.
        • Knowles J.A.
        • Vaccarino F.M.
        • Farnham P.J.
        • Crawford G.E.
        • et al.
        The PsychENCODE project.
        Nat Neurosci. 2015; 18: 1707-1712
        • Gamazon E.R.
        • Wheeler H.E.
        • Shah K.P.
        • Mozaffari S.V.
        • Aquino-Michaels K.
        • Carroll R.J.
        • et al.
        A gene-based association method for mapping traits using reference transcriptome data.
        Nat Genet. 2015; 47: 1091-1098
        • Cadwell C.R.
        • Scala F.
        • Li S.
        • Livrizzi G.
        • Shen S.
        • Sandberg R.
        • et al.
        Multimodal profiling of single-cell morphology, electrophysiology, and gene expression using Patch-seq.
        Nat Protoc. 2017; 12: 2531-2553
        • Wu Y.E.
        • Pan L.
        • Zuo Y.
        • Li X.
        • Hong W.
        Detecting activated cell populations using single-cell RNA-seq.
        Neuron. 2017; 96: 313-329
        • Schwartzentruber J.
        • Foskolou S.
        • Kilpinen H.
        • Rodrigues J.
        • Alasoo K.
        • Knights A.J.
        • et al.
        Molecular and functional variation in iPSC-derived sensory neurons.
        Nat Genet. 2018; 50: 54-61
        • Wang P.
        • Mokhtari R.
        • Pedrosa E.
        • Kirschenbaum M.
        • Bayrak C.
        • Zheng D.
        • et al.
        CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells.
        Mol Autism. 2017; 8: 11
        • Camp J.G.
        • Badsha F.
        • Florio M.
        • Kanton S.
        • Gerber T.
        • Wilsch-Brauninger M.
        • et al.
        Human cerebral organoids recapitulate gene expression programs of fetal neocortex development.
        Proc Natl Acad Sci U S A. 2015; 112: 15672-15677
        • Jo J.
        • Xiao Y.
        • Sun A.X.
        • Cukuroglu E.
        • Tran H.D.
        • Goke J.
        • et al.
        Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons.
        Cell Stem Cell. 2016; 19: 248-257

      CHORUS Manuscript

      View Open Manuscript