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. 2022 Jan 1;91(1):102-117.
doi: 10.1016/j.biopsych.2021.02.972. Epub 2021 Mar 23.

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

Gabriëlla A M Blokland  1 , Jakob Grove  2 , Chia-Yen Chen  3 , Chris Cotsapas  4 , Stuart Tobet  5 , Robert Handa  5 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium; David St Clair  6 , Todd Lencz  7 , Bryan J Mowry  8 , Sathish Periyasamy  9 , Murray J Cairns  10 , Paul A Tooney  11 , Jing Qin Wu  12 , Brian Kelly  13 , George Kirov  14 , Patrick F Sullivan  15 , Aiden Corvin  16 , Brien P Riley  17 , Tõnu Esko  18 , Lili Milani  19 , Erik G Jönsson  20 , Aarno Palotie  21 , Hannelore Ehrenreich  22 , Martin Begemann  22 , Agnes Steixner-Kumar  22 , Pak C Sham  23 , Nakao Iwata  24 , Daniel R Weinberger  25 , Pablo V Gejman  26 , Alan R Sanders  26 , Joseph D Buxbaum  27 , Dan Rujescu  28 , Ina Giegling  28 , Bettina Konte  29 , Annette M Hartmann  29 , Elvira Bramon  30 , Robin M Murray  31 , Michele T Pato  32 , Jimmy Lee  33 , Ingrid Melle  34 , Espen Molden  35 , Roel A Ophoff  36 , Andrew McQuillin  37 , Nicholas J Bass  37 , Rolf Adolfsson  38 , Anil K Malhotra  7 ; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Nicholas G Martin  39 , Janice M Fullerton  40 , Philip B Mitchell  41 , Peter R Schofield  40 , Andreas J Forstner  42 , Franziska Degenhardt  43 , Sabrina Schaupp  44 , Ashley L Comes  45 , Manolis Kogevinas  46 , José Guzman-Parra  47 , Andreas Reif  48 , Fabian Streit  49 , Lea Sirignano  49 , Sven Cichon  50 , Maria Grigoroiu-Serbanescu  51 , Joanna Hauser  52 , Jolanta Lissowska  53 , Fermin Mayoral  47 , Bertram Müller-Myhsok  54 , Beata Świątkowska  55 , Thomas G Schulze  56 , Markus M Nöthen  57 , Marcella Rietschel  49 , John Kelsoe  58 , Marion Leboyer  59 , Stéphane Jamain  60 , Bruno Etain  61 , Frank Bellivier  62 , John B Vincent  63 , Martin Alda  64 , Claire O'Donovan  65 , Pablo Cervantes  66 , Joanna M Biernacka  67 , Mark Frye  68 , Susan L McElroy  69 , Laura J Scott  70 , Eli A Stahl  71 , Mikael Landén  72 , Marian L Hamshere  14 , Olav B Smeland  34 , Srdjan Djurovic  73 , Arne E Vaaler  74 , Ole A Andreassen  34 ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bernhard T Baune  75 , Tracy Air  76 , Martin Preisig  77 , Rudolf Uher  65 , Douglas F Levinson  78 , Myrna M Weissman  79 , James B Potash  80 , Jianxin Shi  81 , James A Knowles  82 , Roy H Perlis  83 , Susanne Lucae  84 , Dorret I Boomsma  85 , Brenda W J H Penninx  86 , Jouke-Jan Hottenga  85 , Eco J C de Geus  85 , Gonneke Willemsen  85 , Yuri Milaneschi  86 , Henning Tiemeier  87 , Hans J Grabe  88 , Alexander Teumer  89 , Sandra Van der Auwera  88 , Uwe Völker  90 , Steven P Hamilton  91 , Patrik K E Magnusson  92 , Alexander Viktorin  92 , Divya Mehta  93 , Niamh Mullins  94 , Mark J Adams  95 , Gerome Breen  96 , Andrew M McIntosh  97 , Cathryn M Lewis  98 ; Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium; iPSYCH; David M Hougaard  99 , Merete Nordentoft  100 , Ole Mors  101 , Preben B Mortensen  102 , Thomas Werge  103 , Thomas D Als  104 , Anders D Børglum  104 , Tracey L Petryshen  105 , Jordan W Smoller  83 , Jill M Goldstein  106
Collaborators, Affiliations

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

Gabriëlla A M Blokland et al. Biol Psychiatry. .

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.

Keywords: Bipolar disorder; Genome-wide association study; Genotype-by-sex interaction; Major depressive disorder; Schizophrenia; Sex differences.

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Conflict of interest statement

Disclosures

JG is on the scientific advisory board for and has equity in Cala Health, a neuromodulation company, although this is unrelated to the topic in this study; and TLP is an employee of Concert Pharmaceuticals, also unrelated to this study. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
LD Score Regression estimates of sex-specific SNP-based (a) heritability, h2 (±SE), and (b) genetic correlations, rg (SE).This graph shows h2 and rg estimates for MAF > 0.01. a) Heritability estimates were substantially different between the sexes for SCZ (pFDR = 0.019) and MDD (pFDR = 0.005), but not BIP (pFDR = 0.381). b) SNP-based genetic correlations (rg) between males and females within each disorder ranged between 0.86 and 1 and were significantly different from 1 for SCZ (pFDR = 0.039) and BIP (pFDR = 0.039), but not MDD (pFDR = 0.397). No significant differences in the cross-disorder genetic correlations between males and females, with the exception of rg between BIP and MDD (rgF = 0.42; rgM = 0.04; pFDR = 0.044). Abbreviations: BIP = bipolar disorder; MDD = major depressive disorder; SCZ = schizophrenia; F = females; M = males; LD = linkage disequilibrium; SE = standard error.
Figure 2.
Figure 2.
Cross-disorder Manhattan plot of SNP-by-sex interaction p-values (a) and LocusZoom plot for the NKAIN2 gene locus exhibiting a significant SNP-by-sex interaction effect on cross-disorder risk (b). This graph shows the genome-wide significant result from the cross-disorder omnibus test in ASSET (primary model). Negative log10-transformed p-values for each variant (each dot) (y-axis) are plotted by chromosomal position (x-axis). The red and blue lines represent the thresholds for genome-wide significant association (p = 5×10−8) and suggestive association (p = 1×10−6), respectively. The strongest GxS interaction was found for SNP rs117780815 on chromosome 6 (p=3.2×10−8) driven by BIP and SCZ. The effect was in opposite directions, with the minor allele increasing risk in BIP women and decreasing risk in BIP men, and vice versa in SCZ women and men (Table 2, Supplementary Table 7). Abbreviations: chr = chromosome; cM = centimorgans; Mb = megabases; r2 = linkage disequilibrium level; NKAIN2 = Sodium/Potassium Transporting ATPase Interacting 2
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