Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Depressive Disorder, Major*/genetics ; Schizophrenia*/genetics; Humans ; Toll-Like Receptor 4/genetics ; Whole Genome Sequencing ; Siblings ; Genetic Predisposition to Disease

Schizophrenia and affective disorder are two major complex mental disorders with high heritability. Evidence shows that rare variants with significant clinical impacts contribute to the genetic liability of these two disorders. Also, rare variants associated with schizophrenia and affective disorders are highly personalized; each patient may carry different variants. We used whole genome sequencing analysis to study the genetic basis of two families with schizophrenia and major depressive disorder. We did not detect de novo, autosomal dominant, or recessive pathogenic or likely pathogenic variants associated with psychiatric disorders in these two families. Nevertheless, we identified multiple rare inherited variants with unknown significance in the probands. In family 1, with singleton schizophrenia, we detected four rare variants in genes implicated in schizophrenia, including p.Arg1627Trp of LAMA2 , p.Pro1338Ser of CSMD1 , p.Arg691Gly of TLR4 , and Arg182X of AGTR2 . The p.Arg691Gly of TLR4 was inherited from the father, while the other three were inherited from the mother. In family 2, with two affected sisters diagnosed with major depressive disorder, we detected three rare variants shared by the two sisters in three genes implicated in affective disorders, including p.Ala4551Gly of FAT1 , p.Val231Leu of HOMER3 , and p.Ile185Met of GPM6B . These three rare variants were assumed to be inherited from their parents. Prompted by these findings, we suggest that these rare inherited variants may interact with each other and lead to psychiatric conditions in these two families. Our observations support the conclusion that inherited rare variants may contribute to the heritability of psychiatric disorders.

Genet Med. 2020 Jan;22(1):170-180. (PMID: 31332282)
Front Genet. 2021 Oct 01;12:620496. (PMID: 34659328)
Hum Mutat. 2012 Feb;33(2):316-26. (PMID: 22095942)
Immunol Invest. 2022 Oct;51(7):2009-2024. (PMID: 35815676)
Heart Fail Rev. 2022 Nov;27(6):2137-2153. (PMID: 35133552)
Mol Psychiatry. 2011 Feb;16(2):216-26. (PMID: 20010893)
Psychiatry Investig. 2017 Sep;14(5):687-692. (PMID: 29042896)
Psychol Med. 2021 Oct;51(13):2260-2273. (PMID: 33634770)
Front Mol Neurosci. 2020 Aug 05;13:123. (PMID: 32848593)
Biol Psychiatry. 2000 Feb 1;47(3):240-4. (PMID: 10682221)
J Affect Disord. 2020 Feb 1;262:31-39. (PMID: 31706157)
Clin Genet. 2022 Nov;102(5):369-378. (PMID: 35996207)
Seizure. 2020 Aug;80:145-152. (PMID: 32570172)
Front Genet. 2023 Mar 23;14:1108440. (PMID: 37035742)
Neuroscience. 2021 Jan 1;452:138-152. (PMID: 33186610)
Nucleic Acids Res. 2023 Jan 6;51(D1):D523-D531. (PMID: 36408920)
Clin Genet. 2018 Nov;94(5):419-428. (PMID: 30047143)
Peptides. 2022 May;151:170766. (PMID: 35151768)
Pediatr Nephrol. 2014 Jan;29(1):51-9. (PMID: 23636579)
Neurosci Lett. 2017 Apr 24;647:122-128. (PMID: 28344127)
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jul 1;44:301-11. (PMID: 23587629)
Mol Psychiatry. 2022 Feb;27(2):1111-1119. (PMID: 34782712)
PLoS Genet. 2015 Mar 27;11(3):e1005137. (PMID: 25816005)
Front Psychiatry. 2017 Nov 30;8:268. (PMID: 29249995)
Am J Psychiatry. 2000 Oct;157(10):1552-62. (PMID: 11007705)
J Psychiatry Neurosci. 2016 Apr;41(3):E46-55. (PMID: 27070349)
J Pers Med. 2021 Oct 21;11(11):. (PMID: 34834409)
Endocr Regul. 2022 Feb 18;56(1):55-65. (PMID: 35180818)
Mol Psychiatry. 2003 Mar;8(3):275-87. (PMID: 12660800)
Psychiatry Res. 2020 Mar;285:112727. (PMID: 31837816)
J Alzheimers Dis. 2022;85(3):943-955. (PMID: 34897090)
Front Syst Neurosci. 2022 Jul 01;16:844383. (PMID: 35844244)
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9. (PMID: 16381927)
Neuroscience. 2015 Jul 23;299:1-17. (PMID: 25934039)
Oncol Lett. 2021 May;21(5):398. (PMID: 33777221)
Transl Psychiatry. 2021 Apr 24;11(1):242. (PMID: 33895774)
J Med Genet. 2003 May;40(5):357-9. (PMID: 12746399)
Cell. 2012 Mar 16;148(6):1223-41. (PMID: 22424231)
Onco Targets Ther. 2016 Dec 01;9:7337-7343. (PMID: 27942226)
Clin Genet. 2022 Jan;101(1):134-141. (PMID: 34664255)
Biol Psychiatry. 2011 Jul 1;70(1):35-42. (PMID: 21439553)
Nat Genet. 2011 Sep 18;43(10):969-76. (PMID: 21926974)
Mol Psychiatry. 2008 Mar;13(3):277-84. (PMID: 17938632)
Hum Genet. 2004 Mar;114(4):396; author reply 397. (PMID: 14722754)
Psychol Med. 2021 Oct;51(13):2168-2177. (PMID: 33550997)
J Intern Med. 2008 Sep;264(3):224-36. (PMID: 18793332)
Indian J Psychiatry. 2022 Nov-Dec;64(6):579-587. (PMID: 36714667)
J Hum Genet. 2023 Mar;68(3):175-182. (PMID: 35821406)
Hum Hered. 2010;70(4):269-77. (PMID: 21150212)
Nat Genet. 2012 Dec;44(12):1365-9. (PMID: 23042115)
Am J Hum Genet. 2013 Aug 8;93(2):368-83. (PMID: 23871722)
Exp Ther Med. 2020 Oct;20(4):3462-3468. (PMID: 32905096)
J Neurosci. 2012 Jun 20;32(25):8716-24. (PMID: 22723711)
Mol Psychiatry. 2023 Mar 6;:. (PMID: 36878965)
Mol Psychiatry. 2018 Mar;23(3):639-647. (PMID: 28115744)
Neuromuscul Disord. 2022 Sep;32(9):776-784. (PMID: 35989179)
J Immunol. 2004 Sep 15;173(6):3589-93. (PMID: 15356101)
Genes (Basel). 2022 Dec 10;13(12):. (PMID: 36553598)
Arch Gen Psychiatry. 2003 Dec;60(12):1187-92. (PMID: 14662550)
J Pers Med. 2021 Nov 25;11(12):. (PMID: 34945726)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
Cell Death Dis. 2019 Dec 9;10(12):943. (PMID: 31819047)
J Clin Med. 2022 Feb 09;11(4):. (PMID: 35207180)
Neurosci Biobehav Rev. 2016 May;64:134-47. (PMID: 26905767)
Brain Dev. 2012 Oct;34(9):776-9. (PMID: 22269148)
Psychol Med. 2021 Oct;51(13):2156-2167. (PMID: 33879273)
Am J Med Genet A. 2005 Dec 15;139(3):243-4. (PMID: 16283672)
Mol Neurobiol. 2017 Oct;54(8):5868-5882. (PMID: 27660274)
BMC Psychiatry. 2016 Jul 04;16:206. (PMID: 27377754)
Front Cell Dev Biol. 2021 Oct 11;9:693595. (PMID: 34708032)
Genome Biol. 2007;8(2):206. (PMID: 17316461)
Transl Psychiatry. 2011 Aug 30;1:e36. (PMID: 22832610)
Addict Biol. 2016 May;21(3):613-33. (PMID: 25916683)
Science. 2002 Jun 28;296(5577):2401-3. (PMID: 12089445)
Schizophr Res. 2008 Dec;106(2-3):218-28. (PMID: 18774265)
Cardiovasc Toxicol. 2022 Apr;22(4):311-325. (PMID: 35211833)
J Pers Med. 2022 Jun 20;12(6):. (PMID: 35743796)
Brain Sci. 2023 Jan 11;13(1):. (PMID: 36672107)
Biol Psychiatry. 2022 Apr 15;91(8):709-717. (PMID: 34974922)
Genes (Basel). 2020 Oct 26;11(11):. (PMID: 33114535)
Genome Res. 2001 May;11(5):863-74. (PMID: 11337480)
Nat Neurosci. 2018 Jan;21(1):16-18. (PMID: 29230059)
Nat Methods. 2014 Apr;11(4):361-2. (PMID: 24681721)
BMC Psychiatry. 2019 Apr 15;19(1):113. (PMID: 30987620)
Schizophr Res. 2020 Feb;216:288-294. (PMID: 31813803)
Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512)
Hum Hered. 2012;74(3-4):215-25. (PMID: 23594499)
PLoS One. 2022 Jun 13;17(6):e0269130. (PMID: 35696356)
Biomed J. 2021 Dec;44(6):748-751. (PMID: 34450347)
Neurochem Int. 2012 Oct;61(5):731-8. (PMID: 22749857)
Pediatr Nephrol. 2022 Oct;37(10):2231-2243. (PMID: 35122119)
Front Neurosci. 2014 Nov 06;8:331. (PMID: 25414627)
Schizophr Bull. 2017 Oct 21;43(6):1304-1314. (PMID: 28525603)
Neurotox Res. 2008 Oct;14(2-3):113-20. (PMID: 19073419)
Trends Genet. 2022 Sep;38(9):895-903. (PMID: 35410794)
Mol Cell Neurosci. 2001 Dec;18(6):593-605. (PMID: 11749036)
BMC Med. 2022 Dec 8;20(1):474. (PMID: 36482464)
Mol Psychiatry. 2019 Apr;24(4):523-535. (PMID: 29955165)
J Comp Neurol. 1996 Jul 08;370(4):465-78. (PMID: 8807448)
Int J Mol Sci. 2021 Dec 31;23(1):. (PMID: 35008879)
J Pers Med. 2020 Dec 15;10(4):. (PMID: 33333793)
Mol Psychiatry. 2007 Oct;12(10):899-900. (PMID: 17895925)
Eur Arch Psychiatry Clin Neurosci. 2022 Oct;272(7):1219-1228. (PMID: 35532796)
Mol Psychiatry. 2006 Apr;11(4):372-83. (PMID: 16402135)
ACS Omega. 2021 Sep 04;6(37):24128-24138. (PMID: 34568691)
J Affect Disord. 2022 Aug 1;310:213-222. (PMID: 35533776)
Trends Genet. 2018 Sep;34(9):666-681. (PMID: 29941292)
Biol Open. 2021 Jun 15;10(6):. (PMID: 34100899)
Hum Genet. 2004 Jan;114(2):211-3. (PMID: 14598163)
J Pers Med. 2021 Dec 09;11(12):. (PMID: 34945806)
Clin Genet. 2022 Nov;102(5):434-437. (PMID: 35861186)
Front Neurol. 2022 Jul 26;13:951659. (PMID: 35959384)
Cell. 2020 Feb 6;180(3):568-584.e23. (PMID: 31981491)
Mol Psychiatry. 2023 Jan 26;:. (PMID: 36702864)
Curr Opin Genet Dev. 2021 Jun;68:57-63. (PMID: 33752146)
Psychiatr Genet. 2022 Jun 1;32(3):125-130. (PMID: 35353798)
Transl Psychiatry. 2017 Apr 11;7(4):e1089. (PMID: 28398343)
Psychiatry Clin Neurosci. 2015 Feb;69(2):65-76. (PMID: 25319632)

CORPG3J0311 Linkou Chang Gung Memorial Hospital; CORPG3J0312 Linkou Chang Gung Memorial Hospital; CORPG3J0313 Linkou Chang Gung Memorial Hospital; MOST 107-2314-B-182-057-MY2 Ministry of Science and Technology, Taiwan

Keywords: genetics; heritability; major depression; oligogenic; rare mutations; schizophrenia

0 (Toll-Like Receptor 4)

Date Created: 20230729 Date Completed: 20230731 Latest Revision: 20230801

20231215

PMC10380944

10.3390/ijms241411777

37511534