Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Gandal, Michael J.; Haney, Jillian R.; Parikshak, Neelroop N.; Leppä, Virpi; Ramaswami, Gokul; Hartl, Christopher; Schork, Andrew J.; Appadurai, Vivek; Buil, Alfonso; Werge, Thomas; Liu, Chun Yu; White, Kevin P.; Horvath, Steve; Geschwind, Daniel H.

doi:10.1126/science.aad6469

Cited by 920 publications

(829 citation statements)

References 97 publications

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“…These results also support the recent cross-disorder analysis of gene expression where the mitochondrial and neuronal gene coexpression module was shared between BD and SZ cortical regions [49], and the shared genes were downregulated, independent of antipsychotic treatment [50]. …”

Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 76%

“…In a recent cross-disorder analysis of gene expression, the mitochondrial and neuronal gene coexpression module was shared between BD and SZ cortical regions [49], and the shared genes were downregulated, independent of antipsychotic treatment [50]. Not all recent studies of mitochondrial-related pathways reported an association with SZ.…”

Section: Mitochondrial Genes In the Nuclear Genome And Szmentioning

confidence: 99%

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Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

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Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genessupporting

confidence: 76%

Section: Mitochondrial Genes In the Nuclear Genome And Szmentioning

confidence: 99%

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

et al. 2019

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“…Coexposing mice shortly after birth to cypermethrin (a pyrethroid) and endosulfan altered levels of neuroproteins and resulted in neurobehavioral abnormalities 12. Gene expression of mouse cortical neurons was altered by certain fungicides and resembled transcriptional changes thought to underlie development of autism spectrum disorder 214. Translational research connecting toxicological and animal studies with findings from epidemiological studies is needed to identify the specific modes of action of pesticides relevant for the pathogenesis of autism spectrum disorder 6566676869…”

Section: Discussionmentioning

confidence: 99%

Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study

Ehrenstein

Ling

Cui

et al. 2019

BMJ

215

165

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Objective To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder. Design Population based case-control study. Setting California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics. Population 2961 individuals with a diagnosis of autism spectrum disorder based on the Diagnostic and Statistical Manual of Mental Disorders , fourth edition, revised (up to 31 December 2013), including 445 with intellectual disability comorbidity, were identified through records maintained at the California Department of Developmental Services and linked to their birth records. Controls derived from birth records were matched to cases 10:1 by sex and birth year. Exposure Data from California state mandated Pesticide Use Reporting were integrated into a geographic information system tool to estimate prenatal and infant exposures to pesticides (measured as pounds of pesticides applied per acre/month within 2000 m from the maternal residence). 11 high use pesticides were selected for examination a priori according to previous evidence of neurodevelopmental toxicity in vivo or in vitro (exposure defined as ever v never for each pesticide during specific developmental periods). Main outcome measure Odds ratios and 95% confidence intervals using multivariable logistic regression were used to assess associations between pesticide exposure and autism spectrum disorder (with or without intellectual disabilities) in offspring, adjusting for confounders. Results Risk of autism spectrum disorder was associated with prenatal exposure to glyphosate (odds ratio 1.16, 95% confidence interval 1.06 to 1.27), chlorpyrifos (1.13, 1.05 to 1.23), diazinon (1.11, 1.01 to 1.21), malathion (1.11, 1.01 to 1.22), avermectin (1.12, 1.04 to 1.22), and permethrin (1.10, 1.01 to 1.20). For autism spectrum disorder with intellectual disability, estimated odds ratios were higher (by about 30%) for prenatal exposure to glyphosate (1.33, 1.05 to 1.69), chlorpyrifos (1.27, 1.04 to 1.56), diazinon (1.41, 1.15 to 1.73), permethrin (1.46, 1.20 to 1.78), methyl bromide (1.33, 1.07 to 1.64), and myclobutanil (1.32, 1.09 to 1.60); exposure in the first year of life increased the odds for the disorder with comorbid intellectual disability by up to 50% for some pesticide substances. Conclusion Findings suggest that an offspring’s risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother’s residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure. Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability.

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“…Using gene coexpression network analysis, they showed support for gene networks involved in neurobiological functions that had already been suggested by other studies like the ARC protein complex, targets of FMRP, neuronal markers, postsynaptic density proteins, and NMDA receptors. Most recently, Gandal et al [138] applied transcriptomic analysis to further explore the overlap between psychiatric disorders. They identified patterns of both shared and distinct gene expression perturbations and similar to reported polygenic overlaps, they found strong overlaps with BD autism and MDD in order of overlap strength and reported specific expression patterns.…”

Section: Insights From Transcriptome Studiesmentioning

confidence: 99%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Cited by 920 publications

References 97 publications

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study

Recent Advances in the Genetics of Schizophrenia

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