Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

被引：68

作者：

Blokland, Gabriella A. M. ^{[1
,8
,9
,10
,11
]}

Grove, Jakob ^{[63
,68
,69
]}

Chen, Chia-Yen ^{[8
,9
,12
]}

Cotsapas, Chris ^{[11
,21
,22
]}

Tobet, Stuart ^{[13
,23
]}

Handa, Robert ^{[13
,23
]}

St Clair, David ^{[75
]}

Lencz, Todd ^{[24
,25
,26
]}

Mowry, Bryan J. ^{[87
,88
]}

Periyasamy, Sathish ^{[87
,92
]}

Cairns, Murray J. ^{[93
,94
,95
]}

Tooney, Paul A. ^{[93
,94
,95
]}

Wu, Jing Qin ^{[93
,94
]}

Kelly, Brian ^{[95
]}

Kirov, George ^{[76
]}

Sullivan, Patrick F. ^{[36
,37
,102
]}

Corvin, Aiden ^{[106
]}

Riley, Brien P. ^{[38
,39
]}

Esko, Tonu ^{[11
,14
,15
,107
]}

Milani, Lili ^{[14
,107
]}

Jonsson, Erik G. ^{[103
,108
]}

Palotie, Aarno ^{[8
,9
,11
,117
]}

Ehrenreich, Hannelore ^{[118
]}

Begemann, Martin ^{[118
]}

Steixner-Kumar, Agnes ^{[118
]}

Sham, Pak C. ^{[138
,139
,140
]}

Iwata, Nakao ^{[141
]}

Weinberger, Daniel R. ^{[40
,41
,42
,43
,44
]}

Gejman, Pablo, V ^{[47
,48
]}

Sanders, Alan R. ^{[47
,48
]}

Buxbaum, Joseph D. ^{[27
,28
,29
,31
]}

Rujescu, Dan ^{[119
,120
]}

Giegling, Ina ^{[119
,120
]}

Konte, Bettina ^{[119
]}

Hartmann, Annette M. ^{[119
]}

Bramon, Elvira ^{[77
]}

Murray, Robin M. ^{[78
]}

Pato, Michele T. ^{[32
,49
,50
]}

Lee, Jimmy ^{[142
,143
,144
]}

Melle, Ingrid ^{[109
,110
]}

Molden, Espen ^{[111
,112
]}

Ophoff, Roel A. ^{[2
,51
,52
]}

McQuillin, Andrew ^{[82
]}

Bass, Nicholas J. ^{[82
]}

Adolfsson, Rolf ^{[104
]}

Malhotra, Anil K. ^{[24
,25
,26
]}

Martin, Nicholas G.

Fullerton, Janice M. ^{[89
,90
]}

Mitchell, Philip B. ^{[96
,97
]}

Schofield, Peter R. ^{[98
]}

机构：

[1] Maastricht Univ, Fac Hlth Med & Life Sci, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands

[2] Univ Med Ctr Utrecht, Dept Psychiat, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands

[3] Vrije Univ Amsterdam, Dept Biol Psychol Netherlands Twin Register, Amsterdam, Netherlands

[4] Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands

[5] Vrije Univ Med Ctr, Amsterdam, Netherlands

[6] GGZ InGeest, Amsterdam, Netherlands

[7] Erasmus MC, Child & Adolescent Psychiat, Rotterdam, Netherlands

[8] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Dept Psychiat, Boston, MA 02114 USA

[9] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[10] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA

[11] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[12] Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA

[13] Massachusetts Gen Hosp, Innovat Ctr Sex Differences Med Icon, Boston, MA 02114 USA

[14] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[15] Broad Inst MIT & Harvard, Med & Populat Genet, Cambridge, MA 02142 USA

[16] Concert Pharmaceut Inc, Lexington, MA USA

[17] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[18] Massachusetts Gen Hosp, Vincent Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA

[19] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA

[20] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[21] Yale Sch Med, Dept Neurol, New Haven, CT USA

[22] Yale Sch Med, Dept Genet, New Haven, CT USA

[23] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA

[24] Feinstein Inst Med Res, Manhasset, NY USA

[25] Zucker Sch Med Hofstra Northwell, Hempstead, NY USA

[26] Zucker Hillside Hosp, Glen Oaks, NY USA

[27] Icahn Sch Med Mt Sinai, Dept Human Genet, New York, NY 10029 USA

[28] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[29] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[30] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[31] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[32] Suny Downstate Med Ctr, Coll Med, Inst Genom Hlth, Brooklyn, NY 11203 USA

[33] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA

[34] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA

[35] New York State Psychiat Inst & Hosp, Div Translat Epidemiol, New York, NY 10032 USA

[36] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[37] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA

[38] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA

[39] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Human & Mol Genet, Richmond, VA USA

[40] Lieber Inst Brain Dev, Baltimore, MD USA

[41] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

[42] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[43] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[44] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD USA

[45] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[46] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[47] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA

[48] North Shore Univ Hlth Syst, Dept Psychiat & Behav Sci, Evanston, IL USA

[49] Univ Southern Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90007 USA

[50] Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90007 USA

来源：

BIOLOGICAL PSYCHIATRY | 2022年 / 91卷 / 01期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; KYNURENINE PATHWAY METABOLISM; AFFECTIVE STIMULI IMPACT; LD SCORE REGRESSION; PARAVENTRICULAR NUCLEUS; GENDER-DIFFERENCES; MAJOR DEPRESSION; DYSPHORIC MOOD; SCHIZOPHRENIA; RISK;

D O I：

10.1016/j.biopsych.2021.02.972

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

BACKGROUND: 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. METHODS: We conducted the largest to date genome-wide genotype-by-sex (GxS) 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. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 x 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 x 10(-8)) for cross-disorder GxS interaction (rs7302529, p = 1.6 x 10(-7); rs73033497, p = 8.8 x 10(-7); rs7914279, p = 6.4 x 10(-7)), implicating various functions. Gene-based analyses identified GxS interaction across disorders (p = 8.97 x 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 x 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 x 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide GXS 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.

引用

页码：102 / 117

页数：16

共 94 条

[1]

Abbott L, 2018, WERE THRILLED ANNOUN

[2] A Comprehensive Family-Based Replication Study of Schizophrenia Genes [J].

Aberg, Karolina A. ;

Liu, Youfang ;

Bukszar, Jozsef ;

McClay, Joseph L. ;

Khachane, Amit N. ;

Andreassen, Ole A. ;

Blackwood, Douglas ;

Corvin, Aiden ;

Djurovic, Srdjan ;

Gurling, Hugh ;

Ophoff, Roel ;

Pato, Carlos N. ;

Pato, Michele T. ;

Riley, Brien ;

Webb, Todd ;

Kendler, Kenneth ;

O'Donovan, Mick ;

Craddock, Nick ;

Kirov, George ;

Owen, Mike ;

Rujescu, Dan ;

St Clair, David ;

Werge, Thomas ;

Hultman, Christina M. ;

Delisi, Lynn E. ;

Sullivan, Patrick ;

van den Oord, Edwin J. .

JAMA PSYCHIATRY, 2013, 70 (06) :573-581

[3] Wnt/β-catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind [J].

Bem, Joanna ;

Brozko, Nikola ;

Chakraborty, Chaitali ;

Lipiec, Marcin A. ;

Kozinski, Kamil ;

Nagalski, Andrzej ;

Szewczyk, Lukasz M. ;

Wisniewska, Marta B. .

FEBS LETTERS, 2019, 593 (13) :1654-1674

[4] FINEMAP: efficient variable selection using summary data from genome-wide association studies [J].

Benner, Christian ;

Spencer, Chris C. A. ;

Havulinna, Aki S. ;

Salomaa, Veikko ;

Ripatti, Samuli ;

Pirinen, Matti .

BIOINFORMATICS, 2016, 32 (10) :1493-1501

[5]

Bertschy G, 2016, EUR J PSYCHIAT, V30, P7

[6] A Subset-Based Approach Improves Power and Interpretation for the Combined Analysis of Genetic Association Studies of Heterogeneous Traits [J].

Bhattacharjee, Samsiddhi ;

Rajaraman, Preetha ;

Jacobs, Kevin B. ;

Wheeler, William A. ;

Melin, Beatrice S. ;

Hartge, Patricia ;

Yeager, Meredith ;

Chung, Charles C. ;

Chanock, Stephen J. ;

Chatterjee, Nilanjan .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 90 (05) :821-835

[7] Kv2 Ion Channels Determine the Expression and Localization of the Associated AMIGO-1 Cell Adhesion Molecule in Adult Brain Neurons [J].

Bishop, Hannah I. ;

Cobb, Melanie M. ;

Kirmiz, Michael ;

Parajuli, Laxmi K. ;

Mandikian, Danielle ;

Philp, Ashleigh M. ;

Melnik, Mikhail ;

Kuja-Panula, Juha ;

Rauvala, Heikki ;

Shigemoto, Ryuichi ;

Murray, Karl D. ;

Trimmer, James S. .

FRONTIERS IN MOLECULAR NEUROSCIENCE, 2018, 11

[8] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[9] The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 [J].

Buniello, Annalisa ;

MacArthur, Jacqueline A. L. ;

Cerezo, Maria ;

Harris, Laura W. ;

Hayhurst, James ;

Malangone, Cinzia ;

McMahon, Aoife ;

Morales, Joannella ;

Mountjoy, Edward ;

Sollis, Elliot ;

Suveges, Daniel ;

Vrousgou, Olga ;

Whetzel, Patricia L. ;

Amode, Ridwan ;

Guillen, Jose A. ;

Riat, Harpreet S. ;

Trevanion, Stephen J. ;

Hall, Peggy ;

Junkins, Heather ;

Flicek, Paul ;

Burdett, Tony ;

Hindorff, Lucia A. ;

Cunningham, Fiona ;

Parkinson, Helen .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D1005-D1012

[10] Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects [J].

Byars, Sean G. ;

Stearns, Stephen C. ;

Boomsma, Jacobus J. .

PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2014, 281 (1794)

← 1 2 3 4 5 6 7 8 9 10 →