Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 198 - 208

Published: Jan. 26, 2023

Language: Английский

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Candidate biomarkers in psychiatric disorders: state of the field

World Psychiatry, Journal Year: 2023, Volume and Issue: 22(2), P. 236 - 262

Published: May 9, 2023

The field of psychiatry is hampered by a lack robust, reliable and valid biomarkers that can aid in objectively diagnosing patients providing individualized treatment recommendations. Here we review critically evaluate the evidence for most promising psychiatric neuroscience literature autism spectrum disorder, schizophrenia, anxiety disorders post‐traumatic stress major depression bipolar substance use disorders. Candidate reviewed include various neuroimaging, genetic, molecular peripheral assays, purposes determining susceptibility or presence illness, predicting response safety. This highlights critical gap biomarker validation process. An enormous societal investment over past 50 years has identified numerous candidate biomarkers. However, to date, overwhelming majority these measures have not been proven sufficiently reliable, useful be adopted clinically. It time consider whether strategic investments might break this impasse, focusing on limited number candidates advance through process definitive testing specific indication. Some N170 signal, an event‐related brain potential measured using electroencephalography, subgroup identification within disorder; striatal resting‐state functional magnetic resonance imaging (fMRI) measures, such as connectivity index (SCI) abnormalities (FSA) index, prediction schizophrenia; error‐related negativity (ERN), electrophysiological first onset generalized structural connectomic social disorder. Alternate forms classification may conceptualizing Collaborative efforts allowing inclusion biosystems beyond genetics neuroimaging are needed, online remote acquisition selected naturalistic setting mobile health tools significantly field. Setting benchmarks well‐defined target application, along with development appropriate funding partnership mechanisms, would also crucial. Finally, it should never forgotten that, actionable, will need clinically predictive at individual level viable clinical settings.

Language: Английский

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Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study

Brain Behavior and Immunity, Journal Year: 2021, Volume and Issue: 97, P. 176 - 185

Published: July 16, 2021

Schizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits these disorders likely to be causal, or could explained by reverse causality/residual confounding.We used bi-directional two-sample Mendelian randomization (MR) multi-variable MR (MVMR) analysis examine evidence causality, specificity direction association 20 (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived (BDNF)) schizophrenia, major disorder.Genetically-predicted IL-6 was increased risk schizophrenia in univariable (OR = 1.24; 95% C.I., 1.05-1.47) MVMR 1.08; 1.03-1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα 1.07; 1.01-1.12) IL-9 1.06; 1.01-1.11) were risk. BDNF 0.97; 0.94-1.00) MCP-1 0.96; 0.91-0.99) reduced findings did not survive correction for multiple testing. The CRP-schizophrenia attenuated completely after taking into account 1.02; 0.81-1.28). No significant observed disorder. Evidence from bidirectional support causality.We report potential causal several depression. Some the testing so replication larger samples required. Experimental studies also required further mechanisms, treatment proteins/pathways

Language: Английский

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Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(5), P. 541 - 547

Published: April 11, 2022

Language: Английский

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Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions

Frontiers in Genetics, Journal Year: 2021, Volume and Issue: 12

Published: June 28, 2021

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic environmental factors. It is well-established that they highly heritable disorders, considerable progress has been made identifying their shared distinct risk However, the 15-40% of derived sources less definitively known. Environmental factors have repeatedly investigated often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, cannabis use. There evidence adversity some types infections also BD. Evidence for other in BD weaker due to fewer studies smaller sample sizes. Relatively few exposures ever examined BD, additional ones likely remain be discovered. A complete picture how confer these requires an understanding interact. Early gene-by-environment interaction both involved candidate genes were underpowered. Larger samples genome-wide data polygenic scores now offer enhanced prospects reveal interactions contribute disorders. Overall, although identified SZ, extent account total remains unknown. For not well understood merit further investigation. Questions regarding mechanisms by exert effects, ways differ sex. Concurrent investigations needed as we work toward a more comprehensive arise.

Language: Английский

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New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications

World Psychiatry, Journal Year: 2023, Volume and Issue: 22(1), P. 4 - 24

Published: Jan. 14, 2023

Psychiatric genetics has made substantial progress in the last decade, providing new insights into genetic etiology of psychiatric disorders, and paving way for precision psychiatry, which individual profiles may be used to personalize risk assessment inform clinical decision‐making. Long recognized heritable, recent evidence shows that disorders are influenced by thousands variants acting together. Most these commonly occurring, meaning every a each disorder, from low high. A series large‐scale studies have discovered an increasing number common rare robustly associated with major disorders. The most convincing biological interpretation findings implicates altered synaptic function autism spectrum disorder schizophrenia. However, mechanistic understanding is still incomplete. In line their extensive epidemiological overlap, appear exist on continua share large degree one another. This provides further support notion current diagnoses do not represent distinct pathogenic entities, ongoing attempts reconceptualize nosology. also influences range behavioral somatic traits diseases, including brain structures, cognitive function, immunological phenotypes cardiovascular disease, suggesting shared potential importance. Current polygenic score tools, predict susceptibility illness, yet provide clinically actionable information. likely improve coming years, they eventually become part practice, stressing need educate clinicians patients about use misuse. review discusses key possible applications, suggests future directions.

Language: Английский

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Genetic control of RNA splicing and its distinct role in complex trait variation

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(9), P. 1355 - 1363

Published: Aug. 18, 2022

Abstract Most genetic variants identified from genome-wide association studies (GWAS) in humans are noncoding, indicating their role gene regulation. Previous have shown considerable links of GWAS signals to expression quantitative trait loci (eQTLs) but the other regulatory mechanisms, such as splicing QTLs (sQTLs), underexplored. Here, we introduce an sQTL mapping method,  t esting for h eterogeneity between is oform-eQ TL e ffects (THISTLE), with improved power over competing methods. Applying THISTLE together a complementary strategy brain transcriptomic ( n = 2,865) and genotype data, 12,794 genes cis -sQTLs at P < 5 × 10 −8 , approximately 61% which were distinct eQTLs. Integrating data into 12 brain-related complex traits (including diseases), 244 associated through -sQTLs, could not be discovered using corresponding eQTL data. Our study demonstrates most sQTLs regulation transcription variation.

Language: Английский

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Role of the Gut-Brain Axis in the Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

JAMA Psychiatry, Journal Year: 2023, Volume and Issue: 80(4), P. 360 - 360

Published: Feb. 8, 2023

Importance Comorbidities and genetic correlations between gastrointestinal tract diseases psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, degree to which shared determinants are involved in these associations underlying GBA is unclear. Objective To investigate etiology identify genomic loci, genes, pathways. Design, Setting, Participants This genome-wide pleiotropic association study using summary statistics from publicly available data sources was performed various statistical approaches sequentially single-nucleotide variation (SNV; formerly polymorphism [SNP]), gene levels pathways disentangle 4 (inflammatory bowel disease, irritable syndrome, peptic ulcer gastroesophageal reflux disease) 6 (schizophrenia, bipolar disorder, major depressive attention-deficit/hyperactivity posttraumatic stress anorexia nervosa). Data were collected March 10, 2021, August 25, analysis January 8 through May 30, 2022. Main Outcomes Measures The primary outcomes consisted of list disorders. Results Extensive overlaps found among 22 24 trait pairs. Pleiotropic under composite null hypothesis identified 2910 significant SNVs 19 pairs, 83 loci colocalized detected. Gene-based 158 unique candidate highly enriched certain GBA-related phenotypes tissues, whereas pathway enrichment further highlighted primarily involving cell adhesion, synaptic structure function, immune differentiation. Several also causal variants gut microbiomes. Mendelian randomization illustrated vertical pleiotropy across pairwise traits. Notably, many for multiple traits, such 1q32.1 ( INAVA ), 19q13.33 FUT2 11q23.2 NCAM1 1p32.3 LRP8 ). Conclusions Relevance These findings suggest that extensively distributed genome. not only support basis but important implications intervention treatment targets simultaneously.

Language: Английский

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A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility

Cell, Journal Year: 2022, Volume and Issue: 185(18), P. 3390 - 3407.e18

Published: Sept. 1, 2022

Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, discovered brainstem serotonergic cilia of hippocampal CA1 pyramidal neurons. Functionally, these are enriched in ciliary-restricted serotonin receptor, 5-hydroxytryptamine receptor 6 (5-HTR6). cilia-targeted sensor, show that opto- chemogenetic stimulation releases onto cilia. Ciliary 5-HTR6 activates non-canonical G

Language: Английский

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The genetic basis of major depressive disorder

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(6), P. 2254 - 2265

Published: Jan. 26, 2023

The genetic dissection of major depressive disorder (MDD) ranks as one the success stories psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 risk loci and proposing more than 200 candidate genes. However, GWAS results derive from analysis cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating there is large component unique to MDD remains inaccessible phenotyping strategies majority identified approaches unlikely be loci. show inventive uses biobank data, novel imputation methods, combined interviewer cases, can identify contribute episodic severe shifts mood, neurovegetative cognitive changes central MDD. Furthermore, new theories about nature causes MDD, drawing upon advances neuroscience psychology, provide handles on how best interpret exploit mapping results.

Language: Английский

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