Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design, Participants and Ethical Approval
2.2. Schizophrenia-Genetic Association Analysis and Statistics
- Defined Phenotype Data: Participants diagnosed with schizophrenia were classified as the case group, while others were classified as control groups.
- Calculated Allele Counts: All allele counts, including reference and variant alleles from filtered SNPs (genotype data), were calculated for both case and control groups. These results were defined as observed counts.
- Derived Expected Counts: Based on the observed counts, expected counts were derived in a 2 × 2 contingency table, constructed from the number of reference alleles in cases, the number of variant alleles in cases, the number of reference alleles in controls, and the number of variant alleles in controls.
- Calculation of Chi-Squared Statistic: The chi-squared statistic was calculated using the expected and observed count values.
- Determination of Degrees of Freedom: The degrees of freedom for the chi-squared test were determined.
- Derivation of p-Values: p-values were derived from the chi-squared statistic and degrees of freedom.
- Preparation of Data: The phenotype and genotype data prepared were the same as those used in the chi-squared test.
- Loading Data into Lasso Model: Phenotype and genotype data were loaded into the lasso model, with the lambda parameter set to 0.95.
- Calculation of Effect Size: The effect size was calculated using lasso regression.
2.3. Variant Annotations and Functional Analysis
3. Results
3.1. Variants from Association Analysis
3.2. Functional Annotations of Risk Genes
3.3. Pathway Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Group | Schizophrenia a (n = 137) | Control (n = 25,927) | ||
---|---|---|---|---|
Sex | ||||
Male | 63 | (46.0%) | 11,676 | (45.0%) |
Female | 74 | (54.0%) | 14,251 | (55.0%) |
Age | ||||
80–89 | 1 | (0.73%) | 895 | (3.42%) |
70–79 | 5 | (3.65%) | 2970 | (11.36%) |
60–69 | 13 | (9.49%) | 5682 | (21.74%) |
50–59 | 33 | (24.09%) | 5124 | (19.60%) |
40–49 | 40 | (29.20%) | 4096 | (15.67%) |
30–39 | 27 | (19.71%) | 3425 | (13.1%) |
20–29 | 17 | (12.41%) | 3002 | (11.49%) |
<20 | 1 | (0.73%) | 733 | (2.81%) |
CHR | Position | SNP ID | Ref a | Alt b | p-Value c | Odds Ratio ± SD | 95% CI | Effect Size d | Region | Relative Gene |
---|---|---|---|---|---|---|---|---|---|---|
1 | 14175667 | rs12028521 | A | G | 6.72 × 10−6 | 0.53 ± 0.14 | 0.40−0.70 | −0.004 | intergenic | PRDM2; KAZN |
1 | 190853292 | rs1170702 | T | C | 6.80 × 10−6 | 2.22 ± 0.18 | 1.55−3.17 | 0.000 | intergenic | LINC01720; LINC01680 |
2 | 109675309 | rs1010840 | T | C | 7.20 × 10−6 | 1.74 ± 0.12 | 1.36−2.22 | 0.014 | intergenic | SOWAHC; RGPD6 |
4 | 110552210 | rs9997349 | A | G | 3.62 × 10−6 | 2.18 ± 0.17 | 1.55−3.05 | 0.014 | intronic | ENPEP |
8 | 129221357 | rs78144262 | G | A | 2.14 × 10−8 | 2.24 ± 0.15 | 1.68−2.99 | 0.026 | ncRNA_intronic | LINC00977 |
13 | 65637888 | rs11619878 | G | A | 5.71 × 10−7 | 2.25 ± 0.17 | 1.63−3.13 | 0.018 | intergenic | LINC00355; LINC01052 |
13 | 112867397 | rs1556812 | C | G | 1.87 × 10−7 | 2.50 ± 0.18 | 1.75−3.57 | 0.000 | intronic | ATP11A |
15 | 85947722 | rs117010638 | A | C | 6.07 × 10−6 | 2.12 ± 0.17 | 1.52−2.96 | 0.001 | intergenic | MIR548AP; AGBL1 |
19 | 49162083 | rs11083963 | G | A | 7.11 × 10−6 | 1.72 ± 0.12 | 1.36−2.19 | 0.014 | intronic | TRPM4 |
X | 31237060 | rs12859097 | G | T | 5.44 × 10−6 | 2.22 ± 0.18 | 1.56−3.16 | 0.016 | intronic | DMD |
This Study | TPMI a | Twbank b | 1000g c | gnomAD d | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SNP ID | Alt | Case | Control | AFR | AMR | EAS | EUR | AFR | AMR | EAS | FIN | NFE | ||
rs12028521 | G | 0.234 | 0.365 | 0.365 | 0.371 | 0.200 | 0.310 | 0.350 | 0.110 | 0.174 | 0.258 | 0.361 | 0.114 | 0.109 |
rs1170702 | C | 0.128 | 0.062 | 0.060 | 0.059 | - | - | - | - | - | - | - | - | - |
rs1010840 | C | 0.383 | 0.263 | 0.267 | 0.264 | 0.086 | 0.190 | 0.240 | 0.075 | 0.103 | 0.168 | 0.269 | 0.059 | 0.080 |
rs9997349 | G | 0.146 | 0.073 | 0.072 | 0.073 | - | - | - | - | - | - | - | - | - |
rs78144262 | A | 0.215 | 0.109 | 0.111 | 0.119 | - | 0.099 | 0.090 | 0.002 | 0.002 | 0.146 | 0.109 | 0.013 | 0.002 |
rs11619878 | A | 0.157 | 0.076 | 0.078 | 0.076 | 0.430 | 0.410 | 0.086 | 0.500 | 0.443 | 0.384 | 0.082 | 0.501 | 0.518 |
rs1556812 | G | 0.128 | 0.055 | 0.058 | 0.061 | 0.340 | 0.300 | 0.085 | 0.240 | 0.285 | 0.276 | 0.058 | 0.266 | 0.219 |
rs117010638 | C | 0.150 | 0.077 | 0.076 | 0.076 | - | - | 0.090 | 0.012 | 0.000 | 0.000 | 0.073 | 0.059 | 0.004 |
rs11083963 | A | 0.577 | 0.442 | 0.440 | 0.430 | 0.200 | 0.530 | 0.390 | 0.550 | 0.266 | 0.596 | 0.435 | 0.524 | 0.560 |
rs12859097 | T | 0.180 | 0.090 | 0.092 | 0.094 | - | - | - | - | - | - | - | - | - |
Variant and Risk Allele | p-Value | RAF | Beta | Reported Trait | Trait(s) | Study Accession |
---|---|---|---|---|---|---|
rs11619878-G | 1 × 10−7 | 0.511 | 0.163 unit decrease | IgG glycosylation | Serum IgG glycosylation measurement | GCST001848 |
GO_ID | Term | p-Value | Gene |
---|---|---|---|
GO:0006518 | Peptide metabolic process | 0.002 | ENPEP; DMD |
GO:0035609 | C-terminal protein deglutamylation | 0.004 | AGBL1 |
GO:0035610 | Protein side chain deglutamylation | 0.004 | AGBL1 |
GO:0045760 | Positive regulation of action potential | 0.004 | TRPM4 |
GO:0086043 | Bundle of His cell action potential | 0.004 | TRPM4 |
GO:0086045 | Membrane depolarization during AV node cell action potential | 0.004 | TRPM4 |
GO:1904177 | Regulation of adipose tissue development | 0.004 | TRPM4 |
GO:2000169 | Regulation of peptidyl-cysteine S-nitrosylation | 0.004 | DMD |
GO:0003081 | Regulation of systemic arterial blood pressure by renin-angiotensin | 0.005 | ENPEP |
GO:0014819 | Regulation of skeletal muscle contraction | 0.005 | DMD |
GO:0086016 | AV node cell action potential | 0.005 | TRPM4 |
GO:1904181 | Positive regulation of membrane depolarization | 0.005 | TRPM4 |
GO:0010831 | Positive regulation of myotube differentiation | 0.006 | ATP11A |
GO:0035608 | Protein deglutamylation | 0.006 | AGBL1 |
GO:0002709 | Regulation of T cell mediated immunity | 0.008 | TRPM4 |
GO:0002002 | Regulation of angiotensin levels in blood | 0.009 | ENPEP |
GO:0002003 | Angiotensin maturation | 0.009 | ENPEP |
GO:0018410 | C-terminal protein amino acid modification | 0.009 | AGBL1 |
GO:0098660 | Inorganic ion transmembrane transport | 0.009 | TRPM4 |
GO:0098911 | Regulation of ventricular cardiac muscle cell action potential | 0.009 | TRPM4 |
GO:1902307 | Positive regulation of sodium ion transmembrane transport | 0.009 | DMD |
GO:0030502 | Negative regulation of bone mineralization | 0.010 | TRPM4 |
GO:0035774 | Positive regulation of insulin secretion involved in cellular responseto glucose stimulus | 0.010 | TRPM4 |
GO:2000651 | Positive regulation of sodium ion transmembrane transporter activity | 0.010 | DMD |
GO:0035994 | Response to muscle stretch | 0.011 | DMD |
GO:0001990 | Regulation of systemic arterial blood pressure by hormone | 0.012 | ENPEP |
GO:0002407 | Dendritic cell chemotaxis | 0.012 | TRPM4 |
GO:0045907 | Positive regulation of vasoconstriction | 0.012 | TRPM4 |
GO:0010460 | Positive regulation of heart rate | 0.013 | TRPM4 |
GO:0010881 | Regulation of cardiac muscle contraction by regulation of the release ofsequestered calcium ion | 0.013 | DMD |
GO:0036336 | Dendritic cell migration | 0.013 | TRPM4 |
GO:0086012 | Membrane depolarization during cardiac muscle cell action potential | 0.013 | TRPM4 |
GO:0098719 | Sodium ion import across plasma membrane | 0.013 | TRPM4 |
GO:0002724 | Regulation of T cell cytokine production | 0.014 | TRPM4 |
GO:0045823 | Positive regulation of heart contraction | 0.015 | TRPM4 |
GO:0010882 | Regulation of cardiac muscle contraction by calcium ion signaling | 0.016 | DMD |
GO:0033137 | Negative regulation of peptidyl-serine phosphorylation | 0.016 | DMD |
GO:0070168 | Negative regulation of biomineral tissue development | 0.016 | TRPM4 |
GO:1901385 | Regulation of voltage-gated calcium channel activity | 0.016 | DMD |
GO:0010880 | Regulation of release of sequestered calcium ion into cytosol by sarcoplasmicreticulum | 0.017 | DMD |
GO:0002718 | Regulation of cytokine production involved in immune response | 0.018 | TRPM4 |
GO:0030279 | Negative regulation of ossification | 0.018 | TRPM4 |
GO:0034204 | Lipid translocation | 0.018 | ATP11A |
GO:0010830 | Regulation of myotube differentiation | 0.019 | ATP11A |
GO:0032414 | Positive regulation of ion transmembrane transporter activity | 0.019 | DMD |
GO:0043171 | Peptide catabolic process | 0.019 | ENPEP |
GO:0060314 | Regulation of ryanodine-sensitive calcium-release channel activity | 0.019 | DMD |
GO:0098901 | Regulation of cardiac muscle cell action potential | 0.019 | TRPM4 |
GO:0051155 | Positive regulation of striated muscle cell differentiation | 0.020 | ATP11A |
GO:0086004 | Regulation of cardiac muscle cell contraction | 0.020 | TRPM4 |
GO:0061178 | Regulation of insulin secretion involved in cellular response to glucosestimulus | 0.021 | TRPM4 |
GO:0006942 | Regulation of striated muscle contraction | 0.022 | DMD |
GO:0019229 | Regulation of vasoconstriction | 0.022 | TRPM4 |
GO:0035633 | Maintenance of blood-brain barrier | 0.022 | DMD |
GO:0086001 | Cardiac muscle cell action potential | 0.022 | DMD |
GO:1901019 | Regulation of calcium ion transmembrane transporter activity | 0.022 | DMD |
GO:0045332 | Phospholipid translocation | 0.023 | ATP11A |
GO:0045668 | Negative regulation of osteoblast differentiation | 0.023 | TRPM4 |
GO:0055001 | Muscle cell development | 0.024 | DMD |
GO:0060048 | Cardiac muscle contraction | 0.025 | DMD |
GO:0042692 | Muscle cell differentiation | 0.026 | DMD |
GO:0030049 | Muscle filament sliding | 0.028 | DMD |
GO:0032024 | Positive regulation of insulin secretion | 0.028 | TRPM4 |
GO:0033275 | Actin-myosin filament sliding | 0.028 | DMD |
GO:0086091 | Regulation of heart rate by cardiac conduction | 0.029 | TRPM4 |
GO:0060047 | Heart contraction | 0.030 | DMD |
GO:2000649 | Regulation of sodium ion transmembrane transporter activity | 0.030 | DMD |
GO:0001508 | Action potential | 0.033 | DMD |
GO:0098655 | Cation transmembrane transport | 0.033 | TRPM4 |
GO:0043604 | Amide biosynthetic process | 0.038 | DMD |
GO:0045600 | Positive regulation of fat cell differentiation | 0.038 | TRPM4 |
GO:0051279 | Regulation of release of sequestered calcium ion into cytosol | 0.038 | DMD |
GO:0051289 | Protein homotetramerization | 0.038 | TRPM4 |
GO:0006941 | Striated muscle contraction | 0.040 | DMD |
GO:0016925 | Protein sumoylation | 0.040 | TRPM4 |
GO:0030500 | Regulation of bone mineralization | 0.042 | TRPM4 |
GO:0007517 | Muscle organ development | 0.043 | DMD |
GO:0015914 | Phospholipid transport | 0.043 | ATP11A |
GO:1901565 | Organonitrogen compound catabolic process | 0.046 | ENPEP |
Reactome ID | Term | p-Value | Gene |
---|---|---|---|
R-HSA-983712 | Ion channel transport | 0.007 | ATP11A; TRPM4 |
R-HSA-2022377 | Metabolism of angiotensinogen to angiotensins | 0.013 | ENPEP |
R-HSA-3295583 | TRP channels | 0.019 | TRPM4 |
R-HSA-390522 | Striated muscle contraction | 0.024 | DMD |
R-HSA-3000171 | Non-integrin membrane–ECM interactions | 0.030 | DMD |
R-HSA-8955332 | Carboxyterminal post-translational modifications of tubulin | 0.030 | AGBL1 |
R-HSA-9717207 | Sensory perception of sweet, bitter, and umami (glutamate) taste | 0.030 | TRPM4 |
R-HSA-9035034 | RHOF GTPase cycle | 0.031 | SOWAHC |
R-HSA-9717189 | Sensory perception of taste | 0.035 | TRPM4 |
R-HSA-936837 | Ion transport by P-type ATPases | 0.039 | ATP11A |
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Huang, C.-C.; Wang, Y.-G.; Hsu, C.-L.; Yeh, T.-C.; Chang, W.-C.; Singh, A.B.; Yeh, C.-B.; Hung, Y.-J.; Hung, K.-S.; Chang, H.-A. Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population. Medicina 2024, 60, 1271. https://doi.org/10.3390/medicina60081271
Huang C-C, Wang Y-G, Hsu C-L, Yeh T-C, Chang W-C, Singh AB, Yeh C-B, Hung Y-J, Hung K-S, Chang H-A. Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population. Medicina. 2024; 60(8):1271. https://doi.org/10.3390/medicina60081271
Chicago/Turabian StyleHuang, Chih-Chung, Yi-Guang Wang, Chun-Lun Hsu, Ta-Chuan Yeh, Wei-Chou Chang, Ajeet B. Singh, Chin-Bin Yeh, Yi-Jen Hung, Kuo-Sheng Hung, and Hsin-An Chang. 2024. "Identification of Schizophrenia Susceptibility Loci in the Urban Taiwanese Population" Medicina 60, no. 8: 1271. https://doi.org/10.3390/medicina60081271