Genome-Wide Association Study of Clinical Dimensions of Schizophrenia: Polygenic Effect on Disorganized Symptoms
Abstract
Objective
Method
Results
Conclusions
Method
Clinical Sample and Assessments
Sign/Symptom | Factor Loadings | ||
---|---|---|---|
Positive | Negative/Disorganized | Mood | |
Delusions | 0.836 | 0.288 | 0.233 |
Paranoia | 0.773 | 0.243 | 0.188 |
Hallucinations | 0.779 | 0.088 | −0.108 |
Control delusions | 0.546 | 0.156 | 0.148 |
Conversing/commenting/continuous hallucinations | 0.746 | 0.012 | −0.066 |
Abnormal perception of thought | 0.504 | 0.100 | 0.118 |
Blunted affect | 0.145 | 0.668 | −0.157 |
Poverty of speech | 0.076 | 0.707 | −0.162 |
Formal thought disorder | 0.175 | 0.597 | 0.084 |
Bizarre behavior | 0.188 | 0.565 | 0.114 |
Depression | 0.185 | −0.283 | 0.450 |
Mania | −0.033 | 0.063 | 0.897 |
Depression with psychosis | 0.263 | −0.172 | 0.465 |
Mania with psychosis | 0.015 | 0.140 | 0.934 |
DNA Extraction and Genotyping
Factor Analysis of the Lifetime Dimensions of Psychosis Scale
Association Analysis
Pathway Analysis
Polygenic Score Analysis
Symptom Factor | Single-Nucleotide Polymorphisms (SNPs) | Symptom Factorb | |||||
---|---|---|---|---|---|---|---|
Positive | Negative/Disorganized | Mood | |||||
p-Value Threshold (Dimensional GWAS) to Select SNPs | N | p | Variance Explainedc | p | Variance Explainedc | p | Variance Explainedc |
0.0001 | 138 | 0.67 | −1.29E-05 | 0.28 | 8.09E-05 | 0.69 | −1.14E-05 |
0.001 | 654 | 0.46 | −3.80E-05 | 0.25 | 9.32E-05 | 0.04 | −0.00028 |
0.01 | 3,759 | 0.66 | −1.33E-05 | 0.31 | 7.18E-05 | 0.27 | −8.56E-05 |
0.05 | 13,289 | 0.98 | −4.25E-08 | 0.24 | 9.60E-05 | 0.50 | −3.19E-05 |
0.1 | 22,736 | 0.93 | −5.84E-07 | 0.01 | 0.0004 | 0.59 | −2.00E-05 |
0.2 | 38,939 | 0.78 | 5.45E-06 | 0.01 | 0.0005 | ∼1.00 | 3.34E-10 |
0.3 | 52,843 | 0.62 | 1.73E-05 | 0.02 | 0.0004 | 0.97 | −1.09E-07 |
0.4 | 64,993 | 0.75 | 7.07E-06 | 0.01 | 0.0004 | 0.75 | −6.56E-06 |
0.5 | 76,114 | 0.81 | 4.02E-06 | 0.006 | 0.0005 | 0.81 | −4.00E-06 |
1.0 | 110,942 | 0.77 | 6.07E-06 | 0.007 | 0.0005 | 0.73 | −8.38E-06 |
Results
Factor Analysis
GWAS of Symptom Dimensions
SNP | Chromosome/Band | Location (Base Pair) | Beta | p | Closest Gene (Symbol, Distance [base pair], Gene Name) | Function/Relevance |
---|---|---|---|---|---|---|
Positive symptoms | ||||||
rs7233060 | 18q23 | 75,493,367 | 0.1225 | 2.53×10−07 | CTDP1, −47421, CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) phosphatase, subunit 1 | Makes POLR2A available for initiation of gene expression; mutations cause Charcot-Marie-Tooth (demyelinating) disease |
rs17206232 | 5q12.3 | 64,469,156 | 0.1350 | 1.45×10−06 | ADAMTS6, 11162, ADAM metallopeptidase with thrombospondin type 1 motif, 6 | ADAMTS4/ADAMTS5 induce neurite extension in cultured neurons (25) |
rs2323266 | 13q21.2 | 60,863,304 | −0.1032 | 3.13×10−06 | PCDH20, 18515, protocadherin 20 | Neuronal survival, synaptogenesis (26). Hippocampal circuitry formation, synaptic plasticity (27). Variants in PCDH19 associated with epilepsy (28, 29). |
rs10900020 | 10q11.21 | 44,147,203 | −0.1536 | 3.46×10−06 | CXCL12, 38407, chemokine (C-X-C motif) ligand 12 | Diverse roles in neuronal migration, growth factor signaling, neuroprotection (30). Increased GABA, glutamate, dopamine release (31). |
rs10052004 | 5q11.2 | 56,702,257 | −0.09205 | 3.62×10−06 | Intergenic | |
rs959770 | 4p16.3 | 2,365,095 | −0.1198 | 9.40×10−06 | ZFYVE28, within, zinc finger, FYVE domain containing 28 | Regulation of epidermal growth factor receptor activity |
rs11699237 | 20q13.31 | 55,117,403 | 0.1644 | 9.96×10−06 | Intergenic | |
Negative/disorganized symptoms | ||||||
rs11699237 | 20q13.31 | 55,117,403 | 0.1221 | 3.13×10−06 | Intergenic | |
rs1455244 | 18p11.21 | 11,484,199 | −0.06046 | 3.22×10−06 | Intergenic (195 kb upstream of closest gene, GNAL, guanine nucleotide binding protein [G protein], alpha activating activity polypeptide, olfactory type) | Coupled to mesolimbic and mesocortical dopamine-1 receptors (32) |
rs7172342 | 15q22.2 | 59,123,734 | −0.0795 | 3.83×10−06 | RORA, within, RAR-related orphan receptor A | Transcription factor involved in cerebellar dendritic development and synapse formation (33). Decreased expression in autism (34). |
rs4530903 | 6p21.32 | 32,689,867 | 0.09191 | 4.83×10−06 | Between HLA-DRB1 and HLA-DQA1, 35343, −23293, major histocompatibility complex, class II genes | Immunity. Common SNPs in this region are strongly associated with schizophrenia (7, 9, 10, 22). |
rs13278432 | 8q13.2 | 68,884,401 | 0.07197 | 9.65×10−06 | Intergenic | |
Mood symptoms | ||||||
rs1920592 | 12q24.21 | 113,189,969 | −0.1125 | 1.05×10−06 | Intergenic | |
rs4798896 | 18q23 | 74,013,910 | 0.09174 | 3.81×10−06 | Intergenic | |
rs489332 | 9q21.13 | 77,218,166 | −0.1097 | 5.57×10−06 | Intergenic | |
rs1351267 | 3q25.1 | 153,246,391 | 0.08821 | 6.83×10−06 | Intergenic | |
rs10924245 | 1q44 | 243,800,231 | −0.1661 | 6.93×10−06 | KIF26B,within, kinesin family member 26B | Regulation of cell-cell adhesion |
rs17290922 | 16q13 | 55,581,818 | −0.1338 | 7.78×10−06 | NLRC5,within, nucleotide-binding oligomerization domains 27 | Induce major histocompatibility class-I genes (35) |
rs4702765 | 5p15.2 | 10,980,604 | 0.2237 | 1.06×10−05 | CTNND2, 44347, catenin (cadherin-associated protein), delta 2 | Binds presenilin-1. Maintenance of dendrites and dendritic spines (36). Mutations cause cri du chat syndrome (37). Rare copy number variant observed in schizophrenia (38). |
Pathway Analyses
Polygenic Score Analyses
Discussion
Acknowledgments
Footnote
Supplementary Material
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