Dataset Information

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

ABSTRACT:

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 (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.

Results

Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10^-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10^-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10^-7; rs73033497, p = 8.8 × 10^-7; rs7914279, p = 6.4 × 10^-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10^-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10^-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 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 G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions

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.

SUBMITTER: Blokland GAM

PROVIDER: S-EPMC8458480 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Blokland Gabriëlla A M GAM Grove Jakob J Chen Chia-Yen CY Cotsapas Chris C Tobet Stuart S Handa Robert R St Clair David D Lencz Todd T Mowry Bryan J BJ Periyasamy Sathish S Cairns Murray J MJ Tooney Paul A PA Wu Jing Qin JQ Kelly Brian B Kirov George G Sullivan Patrick F PF Corvin Aiden A Riley Brien P BP Esko Tõnu T Milani Lili L Jönsson Erik G EG Palotie Aarno A Ehrenreich Hannelore H Begemann Martin M Steixner-Kumar Agnes A Sham Pak C PC Iwata Nakao N Weinberger Daniel R DR Gejman Pablo V PV Sanders Alan R AR Buxbaum Joseph D JD Rujescu Dan D Giegling Ina I Konte Bettina B Hartmann Annette M AM Bramon Elvira E Murray Robin M RM Pato Michele T MT Lee Jimmy J Melle Ingrid I Molden Espen E Ophoff Roel A RA McQuillin Andrew A Bass Nicholas J NJ Adolfsson Rolf R Malhotra Anil K AK Martin Nicholas G NG Fullerton Janice M JM Mitchell Philip B PB Schofield Peter R PR Forstner Andreas J AJ Degenhardt Franziska F Schaupp Sabrina S Comes Ashley L AL Kogevinas Manolis M Guzman-Parra José J Reif Andreas A Streit Fabian F Sirignano Lea L Cichon Sven S Grigoroiu-Serbanescu Maria M Hauser Joanna J Lissowska Jolanta J Mayoral Fermin F Müller-Myhsok Bertram B Świątkowska Beata B Schulze Thomas G TG Nöthen Markus M MM Rietschel Marcella M Kelsoe John J Leboyer Marion M Jamain Stéphane S Etain Bruno B Bellivier Frank F Vincent John B JB Alda Martin M O'Donovan Claire C Cervantes Pablo P Biernacka Joanna M JM Frye Mark M McElroy Susan L SL Scott Laura J LJ Stahl Eli A EA Landén Mikael M Hamshere Marian L ML Smeland Olav B OB Djurovic Srdjan S Vaaler Arne E AE Andreassen Ole A OA Baune Bernhard T BT Air Tracy T Preisig Martin M Uher Rudolf R Levinson Douglas F DF Weissman Myrna M MM Potash James B JB Shi Jianxin J Knowles James A JA Perlis Roy H RH Lucae Susanne S Boomsma Dorret I DI Penninx Brenda W J H BWJH Hottenga Jouke-Jan JJ de Geus Eco J C EJC Willemsen Gonneke G Milaneschi Yuri Y Tiemeier Henning H Grabe Hans J HJ Teumer Alexander A Van der Auwera Sandra S Völker Uwe U Hamilton Steven P SP Magnusson Patrik K E PKE Viktorin Alexander A Mehta Divya D Mullins Niamh N Adams Mark J MJ Breen Gerome G McIntosh Andrew M AM Lewis Cathryn M CM Hougaard David M DM Nordentoft Merete M Mors Ole O Mortensen Preben B PB Werge Thomas T Als Thomas D TD Børglum Anders D AD Petryshen Tracey L TL Smoller Jordan W JW Goldstein Jill M JM

Biological psychiatry 20210323 1

<h4>Background</h4>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.<h4>Methods</h4>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 MD ...[more]

PMID: 34099189

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Project description:ImportanceFamily and genetic approaches have traditionally been used to evaluate our diagnostic concepts. Using a novel method, the family genetic risk score (FGRS), can we validate the genetic architecture of major affective and psychotic disorders in a national Swedish sample?ObjectiveTo determine whether FGRSs, calculated for the entire Swedish population, can elucidate the genetic relationship between major affective and psychotic disorders and clarify the association of genetic risk with important clinical features of disease.Design, setting, and participantsThis cohort study included the native Swedish population born from January 1, 1950, through December 31, 1995, and followed up through December 31, 2017. Data were collected from Swedish population-based primary care, specialist, and hospital registers, including age at first registration for a psychiatric diagnosis and number of registrations for major depression, bipolar disorder, and schizophrenia. Data were analyzed from October 15, 2020, to February 2, 2021.ExposuresFGRSs for major depression, bipolar disorder, and schizophrenia calculated from morbidity risks for disorders in first- through fifth-degree relatives, controlling for cohabitation.Main outcomes and measuresDiagnoses of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other nonaffective psychoses (ONAPs), age at registration, and number of registrations for major depression, bipolar disorder, and schizophrenia. Diagnostic conversion of major depression to bipolar disorder and ONAPs to schizophrenia was assessed by Cox proportional hazards regression models.ResultsThe cohort included 4 129 002 individuals (51.4% male) with a mean (SD) age at follow-up of 45.5 (13.4) years. Mean FGRSs for major depression, bipolar disorder, and schizophrenia produced distinct patterns for major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and ONAPs with large separations between disorders. In major depression, bipolar disorder, and schizophrenia, high FGRSs were associated with early age at onset and high rates of recurrence: a high mean FGRS for bipolar disorder was associated with early age at onset (younger than 25 years, 0.11; 95% CI, 0.11-0.12) and higher recurrence (8 or more registrations, 0.11; 95% CI, 0.11-0.12) in major depression. The schizophrenia FGRS was separately associated with psychotic and nonpsychotic forms of major depression (0.10; 95% CI, 0.06-0.14 vs 0.03; 95% CI, 0.02-0.03) and bipolar disorder (0.22; 95% CI, 0.16-0.28 vs 0.11; 95% CI, 0.09-0.12). The bipolar disorder and schizophrenia FGRSs were associated with conversion from major depression to bipolar disorder (eg, hazard ratio, 1.70 [95% CI, 1.63-1.78] for high vs low bipolar FGRS) and ONAP to schizophrenia (eg, hazard ratio, 1.38 [95% CI, 1.27-1.51] for high vs low schizophrenia FGRS).Conclusions and relevanceIn this Swedish cohort study, the FGRSs for major depression, bipolar disorder, and schizophrenia for the Swedish population clearly separated major affective and psychotic disorders from each other in a larger and more representative patient sample than previously possible. These findings provide possible validation, from a genetic perspective, for these major diagnostic categories. These results replicated and extended prior observations on more limited samples of the association of FGRS with age at onset, recurrence, psychotic subtypes, and diagnostic conversions.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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