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. 2017 Apr 11;7(4):e1089.
doi: 10.1038/tp.2017.61.

Large-scale Interaction Effects Reveal Missing Heritability in Schizophrenia, Bipolar Disorder and Posttraumatic Stress Disorder

Free PMC article

Large-scale Interaction Effects Reveal Missing Heritability in Schizophrenia, Bipolar Disorder and Posttraumatic Stress Disorder

H J Woo et al. Transl Psychiatry. .
Free PMC article


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.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Disease association in independent loci and collective interaction analyses. (a) Independent loci (IL) P-value Pi for schizophrenia (SZ), bipolar disorder (BP) and SZ+BP data. (b) Sample sizes (see Supplementary Table 1). (c) Quantile–quantile plots and inflation factor λg. (d) Variations in the area under curve (AUC) with interaction strength ɛ. Single-nucleotide polymorphisms (SNPs) were selected based on Pi during cross-validation. The mean number of SNPs are shown in legend. (e) Dependence of maximum AUC on mean number of SNPs. (f) Correspondence between AUC and P-value of SNP sets. The red line is linear regression for AUC >0.51. Error bars and vertical lines, 95% confidence interval.
Figure 2
Figure 2
Distribution of pathway and gene association strengths. (af) Pathway-based results for SZ (a and b), BP (c and d) and SZ+BP (e and f) data sets. Each pathway was scored by AUC with no interaction (ɛ=0; IL) and with ɛ-optimized interactions (CL). Green symbols in c and e are CL results for annotated pathways. (g and h) Gene-based results for SZ+BP without (g) and with interactions (h). Symbols for each gene are located at the midpoint of coding regions in corresponding chromosomes. See Table 1 and Supplementary Table 4. The P-value estimates are based on Figure 1f. Dotted lines represent the Bonferroni thresholds. Vertical lines, 95% confidence interval. AUC, area under the curve; BP, bipolar disorder; Carbohydr., carbohydrate; CL, collective loci; CS, chondroitin sulfate; DS, dermatan sulfate; IL, independent loci; metab., metabolism; SZ, schizophrenia.
Figure 3
Figure 3
Pathways highly associated with SZ+BP under collective inference. (ad) Pathways in Figure 2e with area under the curve (AUC) >0.60 organized into Reactome hierarchy. See Supplementary Table 3 for full list. Genes of genome-wide significance under collective inference (Figure 2h and Supplementary Table 4) within each pathway are labeled vertically. Error bars, 95% confidence interval. Activ., activation/activates/activated/activity; AJ, adherens junction; Akt, protein kinase B; Asn, asparagine; biogen., biogenesis; biol., biological; biosynth., biosynthesis; BP, bipolar disorder; CAM, cell adhesion molecule; cell., cellular; comm., communication; CS, chondroitin sulfate; degrad., degradation; dep., dependent; devel., development; DS, dermatan sulfate; DSB, double-strand break; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EPH, erythropoietin-producing hepatocellular carcinoma; Ephrin, EPH receptor interacting proteins; ER, endoplasmic reticulum; ErbB4, erb-b4 receptor tyrosine kinase 4; expr., expression; FCERI, Fc epsilon receptor 1; form., formation; functionaliz., functionalization; GAG, glycosaminoglycan; GPCR, G-protein-coupled receptor; GPVI, glycoprotein VI; GRB, growth factor receptor-bound protein; HDR, homology-directed repair; HOX, homeobox; HR, homologous recombination; HS, heparan sulfate; integ., integration; IFN, interferon; IGF1R, insulin growth factor 1 receptor; IL, interleukin; init., initiation; inter., interaction; LAB, linker for activation of B cells; LAT2, linker for activation of T cells family, member 2; maint., maintenance; MAPK, mitogen-activated protein kinase; med., mediated; memb., membrane; metab., metabolism; mitoch., mitochondrial; MHC, major histocompatibility complex; MK, megakaryocyte; mod., modification/modifying; NCAM, neural CAM; NGF, nerve growth factor; NMD, nonsense-mediated decay; NMDAR, N-methyl-d-aspartate receptor; NF-κB, nuclear factor κB; org., organization; PI3K, phosphatidylinositol-3-kinase; phosphor., phosphorylation; pol, polymerase; proc., processing; PTK, protein tyrosine kinase; R., receptor; RAF, rapidly accelerated fibrosarcoma; reg., regulated/regulation; resp., response; SCF, stem cell factor; SHC, Src homology domain-containing; sig., signaling; SLC, solute-carrier; SOS, son of sevenless; SSA, single-strand annealing; SUMO, small ubiquitin-like modifiers; synth., synthesis; sys., system; SZ, schizophrenia; TCF, T cell factor; TGF, transforming growth factor; TNFR, tumor necrosis factor receptor; TP53, tumor protein p53; transcr., transcription; transl., translation; transmemb., transmembrane; transm., transmission; transp., transport; TSR, thrombospondin type 1 repeat domain-containing; thru, through; VEGF, vascular endothelial growth factor.
Figure 4
Figure 4
Pathways highly ranked (AUC>0.54 or P<2 × 10−3) in the PTSD MRS data set (a and b). Dotted horizontal line represents the Bonferroni threshold. FDR <0.042 for pathways shown. Error bars are 95% confidence interval for AUC. ALA, α-linolenic acid; AUC, area under the curve; carboxyl., carboxylation; CoA, coenzyme A; degrad., degradation; ER, endoplasmic reticulum; FA, fatty acid; FDR, false discovery rate; GABA, γ-aminobutyic acid; GLI3R, GLI family zinc finger 3 repressor; HRR, homologous recombination repair; LA, linoleic acid; MAPK, mitogen-activated protein kinase; MRS, Marine Resilience Study; NADPH, nitotinamide adenine dinucleotide phosphate; ncRNA, noncoding RNA; NT, neurotransmitter; NuMA, nuclear mitotic apparatus; PIPs, phosphatidylinositol phosphates; PPAR, peroxisome proliferator-activated receptor; prog., programmed; prot., protein; PTSD, posttraumatic stress disorder; sep. separation; snRNP, small nuclear ribonucleoprotein; synth., synthesis; TAG, triacylglycerol.

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