Exploring the genetic overlap between twelve psychiatric disorders

Romero, Cato; Werme, Josefin; Jansen, Philip R.; Stein, Murray B.; Levey, Daniel F.; Polimanti, Renato; Leeuw, Christiaan de; Posthuma, Daniëlle; Nagel, Mats; Sluis, Sophie van der

doi:10.1038/s41588-022-01245-2

Cited by 53 publications

(41 citation statements)

References 54 publications

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“…To our knowledge, the enrichment of SNP-annotations related to conserved genomic regions is the first of its kind for traits along the suicidality spectrum but was consistent across approaches. The magnitude of enrichment also was consistent with those reported for MDD [44] and across psychiatric disorders more broadly [47]. In the context of loci identified in GWAS of major depression, genes found in conserved regions of the genome were part of networks relevant for organismal development and function across the lifetime such as synaptic function and brain development [48,49].…”

Section: Discussionsupporting

confidence: 75%

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

et al. 2023

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Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry: thought life was not worth living (TLNWL), thoughts of self-harm, actual self-harm, and attempted suicide. A new trait for suicidal thoughts and behaviors was constructed first, phenotypically, by aggregating the previous four traits (termed “suicidality”) and second, genetically, by using genomic structural equation modeling (gSEM; termed S-factor). Suicidality and S-factor were compared using SNP-heritability (h2) estimates, genetic correlation (rg), partitioned h2, effect size distribution, transcriptomic correlations (ρGE) in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit (χ2 = 0.21, AIC = 16.21, CFI = 1.00, SRMR = 0.024). Suicidality (h2 = 7.6%) had higher h2 than the S-factor (h2 = 2.54, Pdiff = 4.78 × 10−13). Although the S-factor had a larger number of non-null susceptibility loci (πc = 0.010), these loci had small effect sizes compared to those influencing suicidality (πc = 0.005, Pdiff = 0.045). The h2 of both traits was enriched for conserved biological pathways. The rg and ρGE support highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerke’s R2 = 8.56%, P = 0.009 (PGSsuicidality) and Nagelkerke’s R2 = 7.48%, P = 0.045 (PGSS-factor). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future genetic study designs interested in common genetic factors among different suicide related phenotypes.

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Section: Discussionsupporting

confidence: 75%

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

et al. 2023

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“…In this study we have investigated the role of rbfox1 in neurodevelopmental and psychiatric disorders by studying the behavioural effects of loss of rbfox1 function in zebrafish. This gene has previously been reported to be highly pleiotropic, contributing to several psychiatric disorders 13,14,28 . In addition, we have validated zebrafish rbfox1 sa15940 and rbfox1 del19 HOM lines as models of neurodevelopmental and psychiatric conditions.…”

Section: Discussionmentioning

confidence: 99%

“…RBFOX1 has not only been related to neurodevelopmental conditions, but increasing evidence points to both 3 rare and common variants in this gene as contributors to several psychiatric and neurological disorders 5,6,[10][11][12] . Interestingly, common variants in RBFOX1 were found significantly associated with the cross-trait phenotype of the most recent genome-wide association studies (GWAS) meta-analysis of psychiatric disorders 13 and RBFOX1 was identified as the second most pleiotropic locus in a previous cross-disorder GWAS meta-analysis, showing association of common variants with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette's syndrome (TS) 14 . Finally, Rbfox1 -/mutant mice present a heightened susceptibility to seizures and neuronal hyperexcitability 15 , and Rbfox1 neuron-specific knockout mice show pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest and lack of aggression 6 , behaviours that are related to different psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic contribution ofrbfox1to psychiatric and neurodevelopmental phenotypes in a zebrafish model

Antón-Galindo

Adel

García‐González

et al. 2023

Preprint

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RBFOX1is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants inRBFOX1have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects ofRBFOX1are not yet understood. Here we found that, in zebrafish,rbfox1is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect ofrbfox1deficiency on behaviour, we usedrbfox1sa15940, arbfox1loss-of-function line. We found thatrbfox1sa15940mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a secondrbfox1loss-of-function line with a different genetic background,rbfox1del19, and found thatrbfox1deficiency affects behaviour similarly in this line, although there were some differences.rbfox1del19mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity thanrbfox1sa15940fish. Taken together, these results suggest thatrbfox1deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present inRbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation ofrbfox1function in behaviour and paves the way to further investigate the mechanisms underlyingrbfox1pleiotropy on the onset of neurodevelopmental and psychiatric disorders.

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“…These results could arise from the sample sizes and power constraints of the available GWAS, as well as, from the higher heritability of certain disorders, including BIP and SCZ. However, very importantly, a recent article found out that MDD shows a very high polygenicity compared to other psychiatric disorders; that is, more genetic variants with weaker effects contribute to the overall genetic signal in MDD, and make the trait less annotatable 69 . In contrast, ADHD, BIP and SCZ showed the highest discoverability and hence a more annotatable genetic signal.…”

Section: Discussionmentioning

confidence: 99%

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders

Cilleros-Portet

Lesseur

Marí

et al. 2023

Preprint

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Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placental cis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placental cis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type-imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.

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Exploring the genetic overlap between twelve psychiatric disorders

Cited by 53 publications

References 54 publications

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

Pleiotropic contribution ofrbfox1to psychiatric and neurodevelopmental phenotypes in a zebrafish model

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders

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