Digenic analysis confirms known and uncovers novel schizophrenia risk genes
Main Article Content
Abstract
Based on an Ashkenazy Jewish case-control cohort for schizophrenia, we carried out (1) genetic association analysis for one variant at a time (GWAS) and (2) digenic analysis by comparing frequencies of genotype pairs between cases and controls. To control for genetic heterogeneity between sexes, we analyzed males and females separately. After pruning of variants in each of males and females, single-variant allelic analysis furnished 9 and 8 statistically significant variants in males and females, respectively, with 3 of these variants being significant in both males and females. Of the 14 distinct variants in males and females, 5 (36%) reside in genes. For digenic analysis, we evaluated all pairs of variants and, for a given variant pair, all nine genotype pairs. For each genotype pair, we applied the Fisher exact test to evaluate whether the given genotype pair was more frequent in cases than controls. We found 76 significant genotype pairs, comprising 36 distinct variants, 20 (56%) of which reside in genes, with many of which being known risk genes, thus lending credence to our approach.
Article Details
How to Cite
NING, Jian; WANG, Xingyu; OTT, Jurg.
Digenic analysis confirms known and uncovers novel schizophrenia risk genes.
Medical Research Archives, [S.l.], v. 12, n. 9, sep. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5723>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i9.5723.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Tandon R, Nasrallah H, Akbarian S, et al. The schizophrenia syndrome, circa 2024: What we know and how that informs its nature. Schizophr Res. Dec 11 2023;264:1-28. doi:10.1016/j.schres.2023.11.015
2. R R, Devtalla H, Rana K, et al. A comprehensive update on genetic inheritance, epigenetic factors, associated pathology, and recent therapeutic intervention by gene therapy in schizophrenia. Chem Biol Drug Des. Jan 2024;103(1):e14374. doi:10.1111/cbdd.14374
3. Liu D, Meyer D, Fennessy B, et al. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations. Nature Genetics. 2023/03/01 2023;55(3):369-376. doi:10.1038/s41588-023-01305-1
4. McClellan JM, King M-C. A tipping point in neuropsychiatric genetics. Neuron. 2021/05/05/ 2021;109(9):1411-1413. doi:10.1016/j.neuron.2021.04.002
5. Lencz T, Yu J, Khan RR, et al. Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia. Neuron. 2021/05/05/ 2021;109(9):1465-1478.e4. doi:10.1016/j.neuron.2021.03.004
6. Schulze TG, McMahon FJ. Genetic association mapping at the crossroads: which test and why? Overview and practical guidelines. Am J Med Genet. Jan 8 2002;114(1):1-11. doi:10.1002/ajmg.10042
7. Uffelmann E, Huang QQ, Munung NS, et al. Genome-wide association studies. Nature Reviews Methods Primers. 2021/08/26 2021;1(1):59. doi:10.1038/s43586-021-00056-9
8. Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. Sep 2008;83(3):311-21. doi:10.1016/j.ajhg.2008.06.024
9. Trubetskoy V, Pardiñas AF, Qi T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022/04/01 2022;604(7906):502-508. doi:10.1038/s41586-022-04434-5
10. Nakamura T, Takata A. The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research. Molecular Psychiatry. 2023/05/01 2023;28(5):1868-1889. doi:10.1038/s41380-023-02005-2
11. Ott J, Sun D. Multilocus association analysis under polygenic models. International journal of data mining and bioinformatics. 2012;6(5):482-9. doi:10.1504/IJDMB.2012.049302
12. Okazaki A, Ott J. Machine learning approaches to explore digenic inheritance. Trends Genet. Oct 2022;38(10):1013-1018. doi:10.1016/j.tig.2022.04.009
13. Zhang Q, Long Q, Ott J. AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects. Research Support, Non-U.S. Gov't. PLoS Comput Biol. Jun 2014;10(6):e1003627. doi:10.1371/journal.pcbi.1003627
14. Zhang Q, Bhatia M, Park T, Ott J. A multi-threaded approach to genotype pattern mining for detecting digenic disease genes. Front Genet. 2023;14:1222517. doi:10.3389/fgene.2023.1222517
15. Lencz T, Guha S, Liu C, et al. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nature communications. 2013/11/19 2013;4(1):2739. doi:10.1038/ncomms3739
16. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. doi:10.1186/s13742-015-0047-8
17. Duncan LE, Ratanatharathorn A, Aiello AE, et al. Largest GWAS of PTSD (N=20,070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. Mar 2018;23(3):666-673. doi:10.1038/mp.2017.77
18. Judson O. Dr. Tatiana's Sex Advice to All Creation: The Definitive Guide to the Evolutionary Biology of Sex. Holt Paperbacks; 2003:320.
19. Carlisle SM, Qin H, Hendrickson RC, et al. Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease. npj Parkinson's Disease. 2021/04/13 2021;7(1):36. doi:10.1038/s41531-021-00180-z
20. Koch E, Kauppi K, Chen C-H. Candidates for drug repurposing to address the cognitive symptoms in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2023/01/10/ 2023;120:110637. doi:10.1016/j.pnpbp.2022.110637
21. Hukic DS, Lavebratt C, Olsson E, et al. Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with psychosis. Psychiatry research. 2017/04// 2017;250:217-220. doi:10.1016/j.psychres.2017.01.030
22. Hajek C, Guo X, Yao J, et al. Coronary Heart Disease Genetic Risk Score Predicts Cardiovascular Disease Risk in Men, Not Women. Circulation: Genomic and Precision Medicine. 2018/10/01 2018;11(10):e002324. doi:10.1161/CIRCGEN.118.002324
23. Saha E, Ben Guebila M, Fanfani V, et al. Gene regulatory networks reveal sex difference in lung adenocarcinoma. Biology of Sex Differences. 2024/08/06 2024;15(1):62. doi:10.1186/s13293-024-00634-y
24. Hjorthøj C, Compton W, Starzer M, et al. Association between cannabis use disorder and schizophrenia stronger in young males than in females. Psychological Medicine. 2023;53(15):7322-7328. doi:10.1017/S0033291723000880
25. Zhao H, Mitra N, Kanetsky PA, Nathanson KL, Rebbeck TR. A practical approach to adjusting for population stratification in genome-wide association studies: principal components and propensity scores (PCAPS). Statistical Applications in Genetics and Molecular Biology. 2018;17(6)doi:10.1515/sagmb-2017-0054
26. Elhaik E. Principal Component Analyses (PCA)-based findings in population genetic studies are highly biased and must be reevaluated. Scientific reports. 2022/08/29 2022;12(1):14683. doi:10.1038/s41598-022-14395-4
27. Grosjean I, Roméo B, Domdom M-A, et al. Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases. Autophagy. 2022/11/02 2022;18(11):2519-2536. doi:10.1080/15548627.2022.2039994
28. Li R, Wang Q, Qiu Y, et al. A Potential Autophagy-Related Competing Endogenous RNA Network and Corresponding Diagnostic Efficacy in Schizophrenia. Front Psychiatry. 2021;12:628361. doi:10.3389/fpsyt.2021.628361
29. Sepúlveda D, Grunenwald F, Vidal A, et al. Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson’s disease. Scientific reports. 2022/02/07 2022;12(1):2038. doi:10.1038/s41598-022-05941-1
30. Tan Y, Zhu J, Hashimoto K. Autophagy-related gene model as a novel risk factor for schizophrenia. Translational Psychiatry. 2024/02/13 2024;14(1):94. doi:10.1038/s41398-024-02767-5
31. Huang C, Guo Y, Li W, et al. Association of the CDKAL1 gene polymorphism with gestational diabetes mellitus in Chinese women. BMJ Open Diabetes Res Care. Apr 2023;11(2). doi:10.1136/bmjdrc-2022-003164
32. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genetics. 2007/06/01 2007;39(6):770-775. doi:10.1038/ng2043
33. Yin XY, Chen P, Zhu HW, et al. The type 2 diabetes mellitus susceptibility gene CDKAL1 polymorphism is associated with depressive symptom in first-episode drug-naive schizophrenic patients. Human Psychopharmacology: Clinical and Experimental. 2021;36(5):e2790. doi:10.1002/hup.2790
34. Li N, Xu Y, Chen H, et al. Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities. EBioMedicine. Jan 2024;99:104940. doi:10.1016/j.ebiom.2023.104940
35. Dogra S, Conn PJ. Metabotropic glutamate receptors as emerging targets for the treatment of schizophreni. Molecular Pharmacology. 2022:MOLPHARM-MR-2021-000460. doi:10.1124/molpharm.121.000460
36. DelaCuesta-Barrutia J, Martínez-Peula O, Rivero G, et al. Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects. Transl Psychiatry. Feb 23 2024;14(1):113. doi:10.1038/s41398-024-02832-z
37. Delphin N, Aust C, Griffiths L, Fernandez F. Epigenetic Regulation in Schizophrenia: Focus on Methylation and Histone Modifications in Human Studies. Genes. 2024;15(3):272. doi:10.3390/genes15030272
38. Rabe F, Smigielski L, Georgiadis F, et al. Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank. medRxiv. 2024:2024.04.05.24305387. doi:10.1101/2024.04.05.24305387
39. Okahisa Y, Ujike H, Kunugi H, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2010/02/01/ 2010;34(1):172-176. doi:10.1016/j.pnpbp.2009.10.020
40. Kang WS, Kim SK, Park JK, et al. Association between promoter polymorphisms of the LIFR gene and schizophrenia with persecutory delusion in a Korean population. Mol Med Rep. Jan 2012;5(1):270-4. doi:10.3892/mmr.2011.618
41. Lobentanzer S, Hanin G, Klein J, Soreq H. Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder. Cell Rep. Oct 15 2019;29(3):764-777.e5. doi:10.1016/j.celrep.2019.09.017
42. Mueller TM, Meador-Woodruff JH. Post-translational protein modifications in schizophrenia. NPJ Schizophr. Mar 2 2020;6(1):5. doi:10.1038/s41537-020-0093-9
43. Chang K, Jian X, Wu C, et al. The contribution of mosaic chromosomal alterations to schizophrenia. Biological Psychiatry. 2024;doi:10.1016/j.biopsych.2024.06.015
44. Ansoleaga B, Garcia-Esparcia P, Pinacho R, Haro JM, Ramos B, Ferrer I. Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. J Psychiatr Res. Jan 2015;60:109-16. doi:10.1016/j.jpsychires.2014.09.012
45. Xiao X, Zheng F, Chang H, et al. The Gene Encoding Protocadherin 9 (PCDH9), a Novel Risk Factor for Major Depressive Disorder. Neuropsychopharmacology. Apr 2018;43(5):1128-1137. doi:10.1038/npp.2017.241
46. Lee CC, Ye R, Tubbs JD, et al. Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia. Front Neurosci. 2022;16:1058359. doi:10.3389/fnins.2022.1058359
47. Yamamoto K, Kuriu T, Matsumura K, et al. Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia. Translational Psychiatry. 2021/10/25 2021;11(1):548. doi:10.1038/s41398-021-01676-1
48. Liu J, Hayden MR, Yang Y. Research progress of RP1L1 gene in disease. Gene. Jun 20 2024;912:148367. doi:10.1016/j.gene.2024.148367
49. Zhuo C, Tian H, Chen J, et al. Associations of cognitive impairment in patients with schizophrenia with genetic features and with schizophrenia-related structural and functional brain changes. Front Genet. 2022;13:880027. doi:10.3389/fgene.2022.880027
50. Akula SK, Marciano JH, Lim Y, et al. TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system. Proceedings of the National Academy of Sciences. 2023/01/24 2023;120(4):e2209964120. doi:10.1073/pnas.2209964120
51. Wang L, Heffner C, Vong Kl, et al. TMEM161B modulates radial glial scaffolding in neocortical development. Proceedings of the National Academy of Sciences. 2023/01/24 2023;120(4):e2209983120. doi:10.1073/pnas.2209983120
52. Yue S, Luo L, Feng Y, et al. Gene-gene interaction and new onset of major depressive disorder: Findings from a Chinese freshmen nested case-control study. Journal of Affective Disorders. 2022/03/01/ 2022;300:505-510. doi:10.1016/j.jad.2021.12.138
53. Merikangas AK, Shelly M, Knighton A, Kotler N, Tanenbaum N, Almasy L. What genes are differentially expressed in individuals with schizophrenia? A systematic review. Molecular Psychiatry. 2022/03/01 2022;27(3):1373-1383. doi:10.1038/s41380-021-01420-7
54. Chen Z, Wang X, Teng Z, et al. Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study. Journal of Affective Disorders. 2024/04/01/ 2024;350:582-589. doi:10.1016/j.jad.2024.01.169
55. Zhang Y, Zhao Y, Song X, et al. Modulation of Stem Cells as Therapeutics for Severe Mental Disorders and Cognitive Impairments. Front Psychiatry. 2020;11:80. doi:10.3389/fpsyt.2020.00080
56. Ye N, Li B, Mao Q, et al. Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target. ACS Chemical Neuroscience. 2019/01/16 2019;10(1):190-200. doi:10.1021/acschemneuro.8b00572
57. Chen G, Xu J, Inoue A, et al. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. Nature communications. 2022/05/02 2022;13(1):2375. doi:10.1038/s41467-022-30081-5
58. Chen G, Xu J, Inoue A, et al. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. Nature communications. May 2 2022;13(1):2375. doi:10.1038/s41467-022-30081-5
59. Del Zompo M, Deleuze JF, Chillotti C, et al. Association study in three different populations between the GPR88 gene and major psychoses. Mol Genet Genomic Med. Mar 2014;2(2):152-9. doi:10.1002/mgg3.54
60. Sargazi S, Heidari Nia M, Saravani R, Jafari Shahroudi M, Jahantigh D, Shakiba M. IGF2BP2 polymorphisms as genetic biomarkers for either schizophrenia or type 2 diabetes mellitus: A case-control study. Gene Reports. 2020/09/01/ 2020;20:100680. doi:10.1016/j.genrep.2020.100680
61. Sánchez-Romo D, Hernández-Vásquez CI, Pereyra-Alférez B, García-García JH. Identification of potential target genes in Homo sapiens, by miRNA of Triticum aestivum: A cross kingdom computational approach. Noncoding RNA Res. Jun 2022;7(2):89-97. doi:10.1016/j.ncrna.2022.03.002
62. Bousman CA, Chana G, Glatt SJ, et al. Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: Convergent pathway analysis findings from two independent samples. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2010/03/01 2010;153B(2):494-502. doi:10.1002/ajmg.b.31006
63. Andrews JL, Goodfellow FJ, Matosin N, et al. Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies. Journal of Psychiatric Research. 2017/07/01/ 2017;90:31-39. doi:10.1016/j.jpsychires.2017.01.009
64. Bousman CA, Luza S, Mancuso SG, et al. Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia. Scientific reports. Feb 19 2019;9(1):2307. doi:10.1038/s41598-019-38490-1
65. Luza S, Opazo CM, Bousman CA, Pantelis C, Bush AI, Everall IP. The ubiquitin proteasome system and schizophrenia. The Lancet Psychiatry. 2020/06/01/ 2020;7(6):528-537. doi:10.1016/S2215-0366(19)30520-6
66. McKinney BA, Reif DM, Ritchie MD, Moore JH. Machine Learning for Detecting Gene-Gene Interactions. Applied Bioinformatics. 2006/06/01 2006;5(2):77-88. doi:10.2165/00822942-200605020-00002
67. Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. Aug 6 2009;460(7256):748-52. doi:10.1038/nature08185
68. MacLean CJ, Sham PC, Kendler KS. Joint linkage of multiple loci for a complex disorder. Am J Hum Genet. Aug 1993;53(2):353-66.
69. Hoh J, Ott J. Scan statistics to scan markers for susceptibility genes. Proc Natl Acad Sci USA. 2000;97(17):9615-7. doi:10.1073/pnas.170179197
70. Hoh J, Ott J. Scan statistics in genome-wide scan for complex trait loci. In: Glaz J, Pozdnyakov V, Wallenstein S, eds. Scan Statistics: Methods and Applications (Statistics for Industry and Technology). Birkhäuser Boston; 2009:197-204.
71. Hoh J, Wille A, Ott J. Trimming, weighting, and grouping SNPs in human case-control association studies. Genome Res. 2001;11(12):2115-9. doi:10.1101/gr.204001
72. Legge SE, Cardno AG, Allardyce J, et al. Associations Between Schizophrenia Polygenic Liability, Symptom Dimensions, and Cognitive Ability in Schizophrenia. JAMA Psychiatry. 2021;78(10):1143-1151. doi:10.1001/jamapsychiatry.2021.1961
73. Landi I, Kaji DA, Cotter L, et al. Prognostic value of polygenic risk scores for adults with psychosis. Nature Medicine. 2021/09/01 2021;27(9):1576-1581. doi:10.1038/s41591-021-01475-7
74. Barbu MC, Viejo-Romero M, Thng G, et al. Pathway-Based Polygenic Risk Scores for Schizophrenia and Associations With Reported Psychotic-like Experiences and Neuroimaging Phenotypes in the UK Biobank. Biological Psychiatry Global Open Science. 2023/10/01/ 2023;3(4):814-823. doi:10.1016/j.bpsgos.2023.03.004
2. R R, Devtalla H, Rana K, et al. A comprehensive update on genetic inheritance, epigenetic factors, associated pathology, and recent therapeutic intervention by gene therapy in schizophrenia. Chem Biol Drug Des. Jan 2024;103(1):e14374. doi:10.1111/cbdd.14374
3. Liu D, Meyer D, Fennessy B, et al. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations. Nature Genetics. 2023/03/01 2023;55(3):369-376. doi:10.1038/s41588-023-01305-1
4. McClellan JM, King M-C. A tipping point in neuropsychiatric genetics. Neuron. 2021/05/05/ 2021;109(9):1411-1413. doi:10.1016/j.neuron.2021.04.002
5. Lencz T, Yu J, Khan RR, et al. Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia. Neuron. 2021/05/05/ 2021;109(9):1465-1478.e4. doi:10.1016/j.neuron.2021.03.004
6. Schulze TG, McMahon FJ. Genetic association mapping at the crossroads: which test and why? Overview and practical guidelines. Am J Med Genet. Jan 8 2002;114(1):1-11. doi:10.1002/ajmg.10042
7. Uffelmann E, Huang QQ, Munung NS, et al. Genome-wide association studies. Nature Reviews Methods Primers. 2021/08/26 2021;1(1):59. doi:10.1038/s43586-021-00056-9
8. Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. Sep 2008;83(3):311-21. doi:10.1016/j.ajhg.2008.06.024
9. Trubetskoy V, Pardiñas AF, Qi T, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022/04/01 2022;604(7906):502-508. doi:10.1038/s41586-022-04434-5
10. Nakamura T, Takata A. The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research. Molecular Psychiatry. 2023/05/01 2023;28(5):1868-1889. doi:10.1038/s41380-023-02005-2
11. Ott J, Sun D. Multilocus association analysis under polygenic models. International journal of data mining and bioinformatics. 2012;6(5):482-9. doi:10.1504/IJDMB.2012.049302
12. Okazaki A, Ott J. Machine learning approaches to explore digenic inheritance. Trends Genet. Oct 2022;38(10):1013-1018. doi:10.1016/j.tig.2022.04.009
13. Zhang Q, Long Q, Ott J. AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects. Research Support, Non-U.S. Gov't. PLoS Comput Biol. Jun 2014;10(6):e1003627. doi:10.1371/journal.pcbi.1003627
14. Zhang Q, Bhatia M, Park T, Ott J. A multi-threaded approach to genotype pattern mining for detecting digenic disease genes. Front Genet. 2023;14:1222517. doi:10.3389/fgene.2023.1222517
15. Lencz T, Guha S, Liu C, et al. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nature communications. 2013/11/19 2013;4(1):2739. doi:10.1038/ncomms3739
16. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. doi:10.1186/s13742-015-0047-8
17. Duncan LE, Ratanatharathorn A, Aiello AE, et al. Largest GWAS of PTSD (N=20,070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. Mar 2018;23(3):666-673. doi:10.1038/mp.2017.77
18. Judson O. Dr. Tatiana's Sex Advice to All Creation: The Definitive Guide to the Evolutionary Biology of Sex. Holt Paperbacks; 2003:320.
19. Carlisle SM, Qin H, Hendrickson RC, et al. Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease. npj Parkinson's Disease. 2021/04/13 2021;7(1):36. doi:10.1038/s41531-021-00180-z
20. Koch E, Kauppi K, Chen C-H. Candidates for drug repurposing to address the cognitive symptoms in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2023/01/10/ 2023;120:110637. doi:10.1016/j.pnpbp.2022.110637
21. Hukic DS, Lavebratt C, Olsson E, et al. Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with psychosis. Psychiatry research. 2017/04// 2017;250:217-220. doi:10.1016/j.psychres.2017.01.030
22. Hajek C, Guo X, Yao J, et al. Coronary Heart Disease Genetic Risk Score Predicts Cardiovascular Disease Risk in Men, Not Women. Circulation: Genomic and Precision Medicine. 2018/10/01 2018;11(10):e002324. doi:10.1161/CIRCGEN.118.002324
23. Saha E, Ben Guebila M, Fanfani V, et al. Gene regulatory networks reveal sex difference in lung adenocarcinoma. Biology of Sex Differences. 2024/08/06 2024;15(1):62. doi:10.1186/s13293-024-00634-y
24. Hjorthøj C, Compton W, Starzer M, et al. Association between cannabis use disorder and schizophrenia stronger in young males than in females. Psychological Medicine. 2023;53(15):7322-7328. doi:10.1017/S0033291723000880
25. Zhao H, Mitra N, Kanetsky PA, Nathanson KL, Rebbeck TR. A practical approach to adjusting for population stratification in genome-wide association studies: principal components and propensity scores (PCAPS). Statistical Applications in Genetics and Molecular Biology. 2018;17(6)doi:10.1515/sagmb-2017-0054
26. Elhaik E. Principal Component Analyses (PCA)-based findings in population genetic studies are highly biased and must be reevaluated. Scientific reports. 2022/08/29 2022;12(1):14683. doi:10.1038/s41598-022-14395-4
27. Grosjean I, Roméo B, Domdom M-A, et al. Autophagopathies: from autophagy gene polymorphisms to precision medicine for human diseases. Autophagy. 2022/11/02 2022;18(11):2519-2536. doi:10.1080/15548627.2022.2039994
28. Li R, Wang Q, Qiu Y, et al. A Potential Autophagy-Related Competing Endogenous RNA Network and Corresponding Diagnostic Efficacy in Schizophrenia. Front Psychiatry. 2021;12:628361. doi:10.3389/fpsyt.2021.628361
29. Sepúlveda D, Grunenwald F, Vidal A, et al. Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson’s disease. Scientific reports. 2022/02/07 2022;12(1):2038. doi:10.1038/s41598-022-05941-1
30. Tan Y, Zhu J, Hashimoto K. Autophagy-related gene model as a novel risk factor for schizophrenia. Translational Psychiatry. 2024/02/13 2024;14(1):94. doi:10.1038/s41398-024-02767-5
31. Huang C, Guo Y, Li W, et al. Association of the CDKAL1 gene polymorphism with gestational diabetes mellitus in Chinese women. BMJ Open Diabetes Res Care. Apr 2023;11(2). doi:10.1136/bmjdrc-2022-003164
32. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genetics. 2007/06/01 2007;39(6):770-775. doi:10.1038/ng2043
33. Yin XY, Chen P, Zhu HW, et al. The type 2 diabetes mellitus susceptibility gene CDKAL1 polymorphism is associated with depressive symptom in first-episode drug-naive schizophrenic patients. Human Psychopharmacology: Clinical and Experimental. 2021;36(5):e2790. doi:10.1002/hup.2790
34. Li N, Xu Y, Chen H, et al. Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities. EBioMedicine. Jan 2024;99:104940. doi:10.1016/j.ebiom.2023.104940
35. Dogra S, Conn PJ. Metabotropic glutamate receptors as emerging targets for the treatment of schizophreni. Molecular Pharmacology. 2022:MOLPHARM-MR-2021-000460. doi:10.1124/molpharm.121.000460
36. DelaCuesta-Barrutia J, Martínez-Peula O, Rivero G, et al. Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects. Transl Psychiatry. Feb 23 2024;14(1):113. doi:10.1038/s41398-024-02832-z
37. Delphin N, Aust C, Griffiths L, Fernandez F. Epigenetic Regulation in Schizophrenia: Focus on Methylation and Histone Modifications in Human Studies. Genes. 2024;15(3):272. doi:10.3390/genes15030272
38. Rabe F, Smigielski L, Georgiadis F, et al. Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank. medRxiv. 2024:2024.04.05.24305387. doi:10.1101/2024.04.05.24305387
39. Okahisa Y, Ujike H, Kunugi H, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2010/02/01/ 2010;34(1):172-176. doi:10.1016/j.pnpbp.2009.10.020
40. Kang WS, Kim SK, Park JK, et al. Association between promoter polymorphisms of the LIFR gene and schizophrenia with persecutory delusion in a Korean population. Mol Med Rep. Jan 2012;5(1):270-4. doi:10.3892/mmr.2011.618
41. Lobentanzer S, Hanin G, Klein J, Soreq H. Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder. Cell Rep. Oct 15 2019;29(3):764-777.e5. doi:10.1016/j.celrep.2019.09.017
42. Mueller TM, Meador-Woodruff JH. Post-translational protein modifications in schizophrenia. NPJ Schizophr. Mar 2 2020;6(1):5. doi:10.1038/s41537-020-0093-9
43. Chang K, Jian X, Wu C, et al. The contribution of mosaic chromosomal alterations to schizophrenia. Biological Psychiatry. 2024;doi:10.1016/j.biopsych.2024.06.015
44. Ansoleaga B, Garcia-Esparcia P, Pinacho R, Haro JM, Ramos B, Ferrer I. Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. J Psychiatr Res. Jan 2015;60:109-16. doi:10.1016/j.jpsychires.2014.09.012
45. Xiao X, Zheng F, Chang H, et al. The Gene Encoding Protocadherin 9 (PCDH9), a Novel Risk Factor for Major Depressive Disorder. Neuropsychopharmacology. Apr 2018;43(5):1128-1137. doi:10.1038/npp.2017.241
46. Lee CC, Ye R, Tubbs JD, et al. Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia. Front Neurosci. 2022;16:1058359. doi:10.3389/fnins.2022.1058359
47. Yamamoto K, Kuriu T, Matsumura K, et al. Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia. Translational Psychiatry. 2021/10/25 2021;11(1):548. doi:10.1038/s41398-021-01676-1
48. Liu J, Hayden MR, Yang Y. Research progress of RP1L1 gene in disease. Gene. Jun 20 2024;912:148367. doi:10.1016/j.gene.2024.148367
49. Zhuo C, Tian H, Chen J, et al. Associations of cognitive impairment in patients with schizophrenia with genetic features and with schizophrenia-related structural and functional brain changes. Front Genet. 2022;13:880027. doi:10.3389/fgene.2022.880027
50. Akula SK, Marciano JH, Lim Y, et al. TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system. Proceedings of the National Academy of Sciences. 2023/01/24 2023;120(4):e2209964120. doi:10.1073/pnas.2209964120
51. Wang L, Heffner C, Vong Kl, et al. TMEM161B modulates radial glial scaffolding in neocortical development. Proceedings of the National Academy of Sciences. 2023/01/24 2023;120(4):e2209983120. doi:10.1073/pnas.2209983120
52. Yue S, Luo L, Feng Y, et al. Gene-gene interaction and new onset of major depressive disorder: Findings from a Chinese freshmen nested case-control study. Journal of Affective Disorders. 2022/03/01/ 2022;300:505-510. doi:10.1016/j.jad.2021.12.138
53. Merikangas AK, Shelly M, Knighton A, Kotler N, Tanenbaum N, Almasy L. What genes are differentially expressed in individuals with schizophrenia? A systematic review. Molecular Psychiatry. 2022/03/01 2022;27(3):1373-1383. doi:10.1038/s41380-021-01420-7
54. Chen Z, Wang X, Teng Z, et al. Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study. Journal of Affective Disorders. 2024/04/01/ 2024;350:582-589. doi:10.1016/j.jad.2024.01.169
55. Zhang Y, Zhao Y, Song X, et al. Modulation of Stem Cells as Therapeutics for Severe Mental Disorders and Cognitive Impairments. Front Psychiatry. 2020;11:80. doi:10.3389/fpsyt.2020.00080
56. Ye N, Li B, Mao Q, et al. Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target. ACS Chemical Neuroscience. 2019/01/16 2019;10(1):190-200. doi:10.1021/acschemneuro.8b00572
57. Chen G, Xu J, Inoue A, et al. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. Nature communications. 2022/05/02 2022;13(1):2375. doi:10.1038/s41467-022-30081-5
58. Chen G, Xu J, Inoue A, et al. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. Nature communications. May 2 2022;13(1):2375. doi:10.1038/s41467-022-30081-5
59. Del Zompo M, Deleuze JF, Chillotti C, et al. Association study in three different populations between the GPR88 gene and major psychoses. Mol Genet Genomic Med. Mar 2014;2(2):152-9. doi:10.1002/mgg3.54
60. Sargazi S, Heidari Nia M, Saravani R, Jafari Shahroudi M, Jahantigh D, Shakiba M. IGF2BP2 polymorphisms as genetic biomarkers for either schizophrenia or type 2 diabetes mellitus: A case-control study. Gene Reports. 2020/09/01/ 2020;20:100680. doi:10.1016/j.genrep.2020.100680
61. Sánchez-Romo D, Hernández-Vásquez CI, Pereyra-Alférez B, García-García JH. Identification of potential target genes in Homo sapiens, by miRNA of Triticum aestivum: A cross kingdom computational approach. Noncoding RNA Res. Jun 2022;7(2):89-97. doi:10.1016/j.ncrna.2022.03.002
62. Bousman CA, Chana G, Glatt SJ, et al. Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: Convergent pathway analysis findings from two independent samples. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2010/03/01 2010;153B(2):494-502. doi:10.1002/ajmg.b.31006
63. Andrews JL, Goodfellow FJ, Matosin N, et al. Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies. Journal of Psychiatric Research. 2017/07/01/ 2017;90:31-39. doi:10.1016/j.jpsychires.2017.01.009
64. Bousman CA, Luza S, Mancuso SG, et al. Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia. Scientific reports. Feb 19 2019;9(1):2307. doi:10.1038/s41598-019-38490-1
65. Luza S, Opazo CM, Bousman CA, Pantelis C, Bush AI, Everall IP. The ubiquitin proteasome system and schizophrenia. The Lancet Psychiatry. 2020/06/01/ 2020;7(6):528-537. doi:10.1016/S2215-0366(19)30520-6
66. McKinney BA, Reif DM, Ritchie MD, Moore JH. Machine Learning for Detecting Gene-Gene Interactions. Applied Bioinformatics. 2006/06/01 2006;5(2):77-88. doi:10.2165/00822942-200605020-00002
67. Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. Aug 6 2009;460(7256):748-52. doi:10.1038/nature08185
68. MacLean CJ, Sham PC, Kendler KS. Joint linkage of multiple loci for a complex disorder. Am J Hum Genet. Aug 1993;53(2):353-66.
69. Hoh J, Ott J. Scan statistics to scan markers for susceptibility genes. Proc Natl Acad Sci USA. 2000;97(17):9615-7. doi:10.1073/pnas.170179197
70. Hoh J, Ott J. Scan statistics in genome-wide scan for complex trait loci. In: Glaz J, Pozdnyakov V, Wallenstein S, eds. Scan Statistics: Methods and Applications (Statistics for Industry and Technology). Birkhäuser Boston; 2009:197-204.
71. Hoh J, Wille A, Ott J. Trimming, weighting, and grouping SNPs in human case-control association studies. Genome Res. 2001;11(12):2115-9. doi:10.1101/gr.204001
72. Legge SE, Cardno AG, Allardyce J, et al. Associations Between Schizophrenia Polygenic Liability, Symptom Dimensions, and Cognitive Ability in Schizophrenia. JAMA Psychiatry. 2021;78(10):1143-1151. doi:10.1001/jamapsychiatry.2021.1961
73. Landi I, Kaji DA, Cotter L, et al. Prognostic value of polygenic risk scores for adults with psychosis. Nature Medicine. 2021/09/01 2021;27(9):1576-1581. doi:10.1038/s41591-021-01475-7
74. Barbu MC, Viejo-Romero M, Thng G, et al. Pathway-Based Polygenic Risk Scores for Schizophrenia and Associations With Reported Psychotic-like Experiences and Neuroimaging Phenotypes in the UK Biobank. Biological Psychiatry Global Open Science. 2023/10/01/ 2023;3(4):814-823. doi:10.1016/j.bpsgos.2023.03.004