Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.
Details
Serval ID
serval:BIB_F58818565413
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.
Journal
Biological psychiatry
Working group(s)
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH
Contributor(s)
Ripke S., Neale B.M., Corvin A., Walters JTR, Farh K.H., Holmans P.A., Lee P., Bulik-Sullivan B., Collier D.A., Huang H., Pers T.H., Agartz I., Agerbo E., Albus M., Alexander M., Amin F., Bacanu S.A., Begemann M., Belliveau R.A., Bene J., Bergen S.E., Bevilacqua E., Bigdeli T.B., Black D.W., Bruggeman R., Buccola N.G., Buckner R.L., Byerley W., Cahn W., Cai G., Campion D., Cantor R.M., Carr V.J., Carrera N., Catts S.V., Chambert K.D., Chan RCK, Chen RYL, Chen EYH, Cheng W., Cheung EFC, Chong S.A., Cloninger C.R., Cohen D., Cohen N., Cormican P., Craddock N., Crowley J.J., Curtis D., Davidson M., Davis K.L., Degenhardt F., Del Favero J., Demontis D., Dikeos D., Dinan T., Djurovic S., Donohoe G., Drapeau E., Duan J., Dudbridge F., Durmishi N., Eichhammer P., Eriksson J., Escott-Price V., Essioux L., Fanous A.H., Farrell M.S., Frank J., Franke L., Freedman R., Freimer N.B., Friedl M., Friedman J.I., Fromer M., Genovese G., Georgieva L., Giegling I., Giusti-Rodríguez P., Godard S., Goldstein J.I., Golimbet V., Gopal S., Gratten J., de Haan L., Hammer C., Hamshere M.L., Hansen M., Hansen T., Haroutunian V., Hartmann A.M., Henskens F.A., Herms S., Hirschhorn J.N., Hoffmann P., Hofman A., Hollegaard M.V., Hougaard D.M., Ikeda M., Joa I., Julià A., Kahn R.S., Kalaydjieva L., Karachanak-Yankova S., Karjalainen J., Kavanagh D., Keller M.C., Kennedy J.L., Khrunin A., Kim Y., Klovins J., Knowles J.A., Konte B., Kucinskas V., Kucinskiene Z.A., Kuzelova-Ptackova H., Kähler A.K., Laurent C., Lee Chee Keong J., Lee S.H., Legge S.E., Lerer B., Li M., Li T., Liang K.Y., Lieberman J., Limborska S., Loughland C.M., Lubinski J., Lönnqvist J., Macek M., Magnusson PKE, Maher B.S., Maier W., Mallet J., Marsal S., Mattheisen M., Mattingsdal M., McCarley R.W., McDonald C., McIntosh A.M., Meier S., Meijer C.J., Melegh B., Melle I., Mesholam-Gately R.I., Metspalu A., Michie P.T., Milani L., Milanova V., Mokrab Y., Morris D.W., Mors O., Murphy K.C., Murray R.M., Myin-Germeys I., Müller-Myhsok B., Nelis M., Nenadic I., Nertney D.A., Nestadt G., Nicodemus K.K., Nikitina-Zake L., Nisenbaum L., Nordin A., O'Callaghan E., O'Dushlaine C., O'Neill F.A., Oh S.Y., Olincy A., Olsen L., Van Os J., Pantelis C., Papadimitriou G.N., Papiol S., Parkhomenko E., Pato M.T., Paunio T., Pejovic-Milovancevic M., Perkins D.O., Pietiläinen O., Pimm J., Pocklington A.J., Powell J., Price A., Pulver A.E., Purcell S.M., Quested D., Rasmussen H.B., Reichenberg A., Reimers M.A., Richards A.L., Roffman J.L., Roussos P., Ruderfer D.M., Salomaa V., Sanders A.R., Schall U., Schubert C.R., Schulze T.G., Schwab S.G., Scolnick E.M., Scott R.J., Seidman L.J., Shi J., Sigurdsson E., Silagadze T., Silverman J.M., Sim K., Slominsky P., Smoller J.W., So H.C., Spencer CCA, Stahl E.A., Stefansson H., Steinberg S., Stogmann E., Straub R.E., Strengman E., Strohmaier J., Stroup T.S., Subramaniam M., Suvisaari J., Svrakic D.M., Szatkiewicz J.P., Söderman E., Thirumalai S., Toncheva D., Tosato S., Veijola J., Waddington J., Walsh D., Wang D., Wang Q., Webb B.T., Weiser M., Wildenauer D.B., Williams N.M., Williams S., Witt S.H., Wolen A.R., Wong EHM, Wormley B.K., Xi H.S., Zai C.C., Zheng X., Zimprich F., Wray N.R., Stefansson K., Visscher P.M., Adolfsson R., Andreassen O.A., Blackwood DHR, Bramon E., Buxbaum J.D., Børglum A.D., Cichon S., Darvasi A., Domenici E., Ehrenreich H., Esko T., Gejman P.V., Gill M., Gurling H., Hultman C.M., Iwata N., Jablensky A.V., Jönsson E.G., Kendler K.S., Kirov G., Knight J., Lencz T., Levinson D.F., Li Q.S., Liu J., Malhotra A.K., McCarroll S.A., McQuillin A., Moran J.L., Mortensen P.B., Periyasamy S., Cairns M.J., Tooney P.A., Wu J.Q., Kelly B., Mowry B.J., Nöthen M.M., Ophoff R.A., Owen M.J., Palotie A., Pato C.N., Petryshen T.L., Posthuma D., Rietschel M., Riley B.P., Rujescu D., Sham P.C., Sklar P., St Clair D., Weinberger D.R., Wendland J.R., Werge T., Daly M.J., Sullivan P.F., O'Donovan M.C., Donnelly P., Barroso I., Blackwell J.M., Bramon E., Brown M.A., Casas J.P., Corvin A., Deloukas P., Duncanson A., Jankowski J., Markus H.S., Mathew C.G., Palmer CNA, Plomin R., Rautanen A., Sawcer S.J., Trembath R.C., Viswanathan A.C., Wood N.W., Spencer CCA, Band G., Bellenguez C., Donnelly P., Freeman C., Giannoulatou E., Hellenthal G., Pearson R., Pirinen M., Strange A., Su Z., Vukcevic D., Langford C., Barroso I., Blackburn H., Bumpstead S.J., Deloukas P., Dronov S., Edkins S., Gillman M., Gray E., Gwilliam R., Hammond N., Hunt S.E., Jayakumar A., Liddle J., McCann O.T., Potter S.C., Ravindrarajah R., Ricketts M., Tashakkori-Ghanbaria A., Waller M., Weston P., Whittaker P., Widaa S., Mathew C.G., Blackwell J.M., Brown M.A., Corvin A., McCarthy M.I., Spencer CCA, Arranz M.J., Bakker S., Bender S., Bramon E., Collier D.A., Crespo-Facorro B., Hall J., Iyegbe C., Jablensky A.V., Kahn R.S., Kalaydjieva L., Lawrie S., Lewis C.M., Lin K., Linszen D.H., Mata I., McIntosh A.M., Murray R.M., Ophoff R.A., Van Os J., Powell J., Rujescu D., Walshe M., Weisbrod M., Wiersma D., Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman JRI, Gaspar H.A., de Leeuw C.A., Steinberg S., Whitehead Pavlides J.M., Trzaskowski M., Byrne E.M., Pers T.H., Holmans P.A., Richards A.L., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Bækvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Bøen E., Boks M.P., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.K., Coryell W., Craig D.W., Cruceanu C., Curtis D., Czerski P.M., Dale A.M., de Jong S., Degenhardt F., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsåshagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Guzman-Parra J., Hamshere M.L., Hautzinger M., Heilbronner U., Herms S., Hipolito M., Hoffmann P., Holland D., Huckins L., Jamain S., Johnson J.S., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Mühleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Olde Loohuis L.M., Ori APS, Oruc L., Ösby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sánchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Weickert C.S., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Hansen C.S., Spijker A.T., St Clair D., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Thompson R.C., Thorgeirsson T.E., Treutlein J., Vedder H., Wang W., Watson S.J., Weickert T.W., Witt S.H., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zöllner S., Wray N.R., Ripke S., Mattheisen M., Trzaskowski M., Byrne E.M., Abdellaoui A., Adams M.J., Agerbo E., Air T.M., Andlauer TFM, Bacanu S.A., Bækvad-Hansen M., Beekman ATF, Bigdeli T.B., Binder E.B., Bryois J., Buttenschøn H.N., Bybjerg-Grauholm J., Cai N., Castelao E., Christensen J.H., Clarke T.K., Coleman JRI, Colodro-Conde L., Couvy-Duchesne B., Craddock N., Crawford G.E., Davies G., Deary I.J., Degenhardt F., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Foo J.C., Forstner A.J., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Hoffmann P., Homuth G., Horn C., Hottenga J.J., Hougaard D.M., Howard D.M., Ising M., Jansen R., Jones I., Jones L.A., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., McGrath P., McGuffin P., Medland S.E., Mehta D., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Mullins N., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Owen M.J., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Pistis G., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Rivera M., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Shi J., Shyn S.I., Sigurdsson E., Sinnamon GCB, Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., Van der Auwera S., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Baune B.T., Berger K., Boomsma D.I., Cichon S., Dannlowski U., de Geus EJC, DePaulo J.R., Domenici E., Domschke K., Esko T., Grabe H.J., Hamilton S.P., Hayward C., Heath A.C., Kendler K.S., Kloiber S., Lewis G., Li Q.S., Lucae S., Madden P.A., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Mortensen P.B., Müller-Myhsok B., Nordentoft M., Nöthen M.M., O'Donovan M.C., Paciga S.A., Pedersen N.L., Penninx BWJH, Perlis R.H., Porteous D.J., Potash J.B., Preisig M., Rietschel M., Schaefer C., Schulze T.G., Smoller J.W., Stefansson K., Tiemeier H., Uher R., Völzke H., Weissman M.M., Werge T., Lewis C.M., Levinson D.F., Breen G., Børglum A.D., Sullivan P.F., Alda M., Blokland GAM, Børglum A.D., Bortolato M., Bralten J., Breen G., Bulik C.M., Burton C.L., Byrne E.M., Carey C.E., Coleman JRI, Davis L.K., Demontis D., Duncan L.E., Edenberg H.J., Erdman L., Faraone S.V., Goldstein J.M., Goleva S.B., Grove J., Guo W., Hübel C., Huckins L.M., Khramtsova E.A., Lee P.H., Martin J., Mathews C.A., Mattheisen M., Neale B.M., Peterson R.E., Petryshen T.L., Robinson E., Smoller J.W., Stahl E., Stranger B.E., Traglia M., Walters R.K., Weiss L.A., Werge T., Winham S.J., Wray N.R., Yao Y., Børglum A.D., Hougaard D.M., Nordentoft M., Mors O., Mortensen P.B., Werge T., Skajaa K., Nöthen M., Owen M., Yolken R.H., Plath N., Mill J., Geschwind D.
ISSN
1873-2402 (Electronic)
ISSN-L
0006-3223
Publication state
Published
Issued date
01/01/2022
Peer-reviewed
Oui
Volume
91
Number
1
Pages
102-117
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Publication Status: ppublish
Abstract
Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.
We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.
Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10 <sup>-8</sup> ), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10 <sup>-6</sup> ) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10 <sup>-7</sup> ; rs73033497, p = 8.8 × 10 <sup>-7</sup> ; rs7914279, p = 6.4 × 10 <sup>-7</sup> ), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10 <sup>-7</sup> ) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10 <sup>-7</sup> ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10 <sup>-7</sup> ) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).
In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.
Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10 <sup>-8</sup> ), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10 <sup>-6</sup> ) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10 <sup>-7</sup> ; rs73033497, p = 8.8 × 10 <sup>-7</sup> ; rs7914279, p = 6.4 × 10 <sup>-7</sup> ), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10 <sup>-7</sup> ) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10 <sup>-7</sup> ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10 <sup>-7</sup> ) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).
In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Keywords
Bipolar Disorder/genetics, Depressive Disorder, Major/genetics, Endothelial Cells, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Psychotic Disorders/genetics, Receptors, Vascular Endothelial Growth Factor, Schizophrenia/genetics, Sex Characteristics, Sulfurtransferases, Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences
Pubmed
Web of science
Create date
15/06/2021 15:52
Last modification date
12/03/2022 7:29
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