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| Open AccessDisease clusters subsequent to anxiety and stress-related disorders and their genetic determinants
In this study, the authors found five disease clusters associated with a prior diagnosis of anxiety/stress-related disorders, and identified several underlying genetic components. These findings may aid mechanistic exploration and risk management for health decline among those patients.
- Xin Han
- , Qing Shen
- & Huan Song
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Article
| Open AccessRadiomic tractometry reveals tract-specific imaging biomarkers in white matter
Diffusion MRI is used for tract-specific microstructural analysis of the white matter. Here, the authors introduce radiomic tractometry (RadTract), enhancing tractometry with radiomics-based imaging biomarkers for improved predictive modelling.
- Peter Neher
- , Dusan Hirjak
- & Klaus Maier-Hein
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Article
| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessHarnessing PROTAC technology to combat stress hormone receptor activation
Stress-hormone receptors are important therapeutic targets for many diseases but the currently clinically approved inhibitor lacks specificity. Here the authors present a stress hormone receptor depletion tool that differs in its mode of action making it specific in counteracting the effects of stress.
- Mahshid Gazorpak
- , Karina M. Hugentobler
- & Katharina Gapp
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Article
| Open AccessNeural circuit selective for fast but not slow dopamine increases in drug reward
The faster a drug enters the brain, the greater its addictive potential. Using simultaneous PET-fMRI in humans, here the authors report a neural circuit responding to fast but not slow dopamine increases from intravenous versus oral methylphenidate delivery.
- Peter Manza
- , Dardo Tomasi
- & Nora D. Volkow
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Article
| Open AccessDiurnal oscillations of MRI metrics in the brains of male participants
Whether temporal variations in brain MRI metrics can be attributed to circadian or diurnal oscillations is unclear. Here, the authors show evidence for diurnal oscillations in MRI metrics in both healthy controls and participants with bipolar disorder.
- Matthew Carlucci
- , Tristram Lett
- & Art Petronis
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Article
| Open AccessRepressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress
Chronic stress can promote breast cancer progression. Here the authors show that a reduction in the levels of Blautia and its metabolite acetate contributes to chronic stress-promoted breast cancer progression, associated with decreased CD8 + T cell anti-tumor immunity.
- Ling Ye
- , Yuanlong Hou
- & Haiping Hao
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Article
| Open AccessUnraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model
The mechanisms of deep-brain stimulation for psychiatric disorders remain insufficiently understood. Here, the authors identified recruitment of cortico-striatal regions, in particular the medial orbitofrontal cortex, as a mechanism to treat compulsivity.
- Bastijn J. G. van den Boom
- , Alfredo Elhazaz-Fernandez
- & Ingo Willuhn
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Article
| Open AccessAssociation between vmPFC gray matter volume and smoking initiation in adolescents
The relationship between brain development and smoking behaviour is not well understood. Here, the authors show an association between volume of the left ventromedial prefrontal cortex and smoking initiation in adolescents.
- Shitong Xiang
- , Tianye Jia
- & Jianfeng Feng
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Article
| Open AccessParsing altered gray matter morphology of depression using a framework integrating the normative model and non-negative matrix factorization
The neuroanatomical heterogeneity of depression is not well understood. Here, the authors identify four latent factors which characterise different patterns of gray matter morphology and are related to clinical symptoms.
- Shaoqiang Han
- , Qian Cui
- & Yong Zhang
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Article
| Open AccessCortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls
The neurochemical basis of compulsive behaviour is not well understood. Here, the authors show that levels of glutamate and GABA in the supplementary motor area and anterior cingulate cortex relate to compulsive behaviour in healthy controls and individuals with OCD.
- Marjan Biria
- , Paula Banca
- & Trevor W. Robbins
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Article
| Open AccessA dorsomedial prefrontal cortex-based dynamic functional connectivity model of rumination
Rumination, which is the tendency to dwell on negative internal states repetitively, is a well-known cognitive style associated with depression. The authors developed a predictive model of rumination and observed that the dorsomedial prefrontal cortex plays an important role in rumination.
- Jungwoo Kim
- , Jessica R. Andrews-Hanna
- & Choong-Wan Woo
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Article
| Open AccessAccelerated biological aging and risk of depression and anxiety: evidence from 424,299 UK Biobank participants
Theory indicates that biological aging may contribute to poor mental health in late life. Here, authors show advanced biological aging may represent a potential risk factor for incident depression/anxiety in midlife and older adults and a potential target for risk assessment and intervention.
- Xu Gao
- , Tong Geng
- & Tao Huang
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Article
| Open AccessPlasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice
The cholinergic circuits involved in pain modulation remain poorly understood. Here, the authors show that reversal of plasticity in the ventral pallidum-basolateral amygdala cholinergic pathway relieves hyperalgesia and depression-like behaviours in a chronic pain mouse model.
- Ya-Wei Ji
- , Zi-Lin Shen
- & Cheng Xiao
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Article
| Open AccessAssociations between mental health, blood pressure and the development of hypertension
Mental and cardiovascular health interact in complex ways. Here, the authors demonstrate an association of blood pressure with depressive symptoms, well-being, and emotion-related brain activity that may be relevant to the development of hypertension.
- H. Lina Schaare
- , Maria Blöchl
- & Arno Villringer
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Article
| Open AccessRegional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents
There are conflicting results on the effectiveness of pharmacologic interventions for suicide prevention in adolescence. Here, the authors show, in a retrospective registry study from Sweden during 2016–2020, that regional utilization rates of clozapine, electroconvulsive therapy and lithium in 15–19-year-olds were associated with lower excess suicide death rates in male adolescents
- Adrian E. Desai Boström
- , Peter Andersson
- & Jussi Jokinen
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Article
| Open AccessFunctional geometry of the cortex encodes dimensions of consciousness
Dimensions of consciousness such as wakefulness or awareness are well established but have not been mapped to the brain. Here, the authors show that dimensions of consciousness are encoded in the functional geometry of the cortex.
- Zirui Huang
- , George A. Mashour
- & Anthony G. Hudetz
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Article
| Open AccessCoordinated cortical thickness alterations across six neurodevelopmental and psychiatric disorders
Neuropsychiatric disorders may have shared features. Here the authors identified hubs of transdiagnostic co-alteration networks using meta-analytical maps of ENIGMA neuroimaging data for six neurodevelopmental and psychiatric disorders.
- M. D. Hettwer
- , S. Larivière
- & S. L. Valk
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Article
| Open AccessGenetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells
The role of the immune system in the pathogenesis of psychiatric disorders is unclear. Here, the authors show that genetic risk variants for multiple psychiatric disorders are enriched in regions of the genome active in the brain and in lymphoid cells, especially stimulated T cells, but not in myeloid cells.
- Mary-Ellen Lynall
- , Blagoje Soskic
- & Ed Bullmore
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Article
| Open AccessRegional gene expression signatures are associated with sex-specific functional connectivity changes in depression
The neural substrates of depression may differ by sex. Here the authors show that depression is associated with distinct brain connectivity changes in men and in women that are explained by sex-specific transcriptomic signatures involving genes previously implicated in synapse function, immune signalling, and depression risk.
- Aleksandr Talishinsky
- , Jonathan Downar
- & Conor Liston
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Article
| Open AccessDerivation and utility of schizophrenia polygenic risk associated multimodal MRI frontotemporal network
Schizophrenia is highly heritable and characterized by widespread brain abnormalities. Here, the authors identify schizophrenia polygenic risk associated multimodal frontotemporal network that can serve as a transdiagnostic brain signature specific to schizophrenia.
- Shile Qi
- , Jing Sui
- & Vince D. Calhoun
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Article
| Open AccessShared mechanisms across the major psychiatric and neurodegenerative diseases
Studying the shared genetic etiology of disease can help improve diagnosis and treatment. Here, the authors find evidence for shared genetic and molecular pathophysiology between several common psychiatric and neurodegenerative diseases using results of 25 GWAS and large-scale human brain transcriptomic and proteomic sequencing.
- Thomas S. Wingo
- , Yue Liu
- & Aliza P. Wingo
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Article
| Open AccessAltered predictive control during memory suppression in PTSD
It remains unclear how predictions of future threat affect memory recall, specifically in the case of post-traumatic stress disorder (PTSD). Here, the authors combined computational modeling and brain connectivity analyses to show that individuals with PTSD have exaggerated predictive control and reduced reactive control in a memory suppression task.
- Giovanni Leone
- , Charlotte Postel
- & Pierre Gagnepain
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| Open AccessKetamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice
Rawat et al. demonstrate that activation of adult-born immature hippocampal neurons is necessary and sufficient for the acute antidepressant effects of low-dose ketamine in mice.
- Radhika Rawat
- , Elif Tunc-Ozcan
- & John A. Kessler
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Article
| Open AccessModeling assortative mating and genetic similarities between partners, siblings, and in-laws
Assortative mating could violate the assumption of random mating used in many genetic studies. Here, the authors study more than 25,000 Norwegian families to find genetic similarity between partners, siblings, and in-laws in genetic factors related to educational attainment, height, and depression.
- Fartein Ask Torvik
- , Espen Moen Eilertsen
- & Eivind Ystrom
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Article
| Open AccessVascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue
The vascular, cellular and molecular changes underlying sex differences in mood disorders are unclear. Here, the authors show that blood-brain barrier dysfunction modulates anxiety- and depressive-like behaviors in female mice and endothelium-specific changes associated with maladaptive responses compared to resilience to stress.
- Laurence Dion-Albert
- , Alice Cadoret
- & Caroline Menard
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Article
| Open AccessPolygenic contribution to the relationship of loneliness and social isolation with schizophrenia
Loneliness and social isolation (LNL-ISO) are associated with schizophrenia. Here the authors demonstrate the role of shared heritability, bidirectional causal relationships and significant differences by sex, illustrating the genomic footprint of social isolation on schizophrenia.
- Álvaro Andreu-Bernabeu
- , Covadonga M. Díaz-Caneja
- & Javier González-Peñas
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Article
| Open AccessAssociations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors
Schizophrenia is a complex disorder where individuals experience different symptoms and outcomes that can be captured by patterns in other diagnoses. Here the authors use computational approaches to summarize these patterns and suggest they are associated with genetic and environmental exposure.
- Morten Dybdahl Krebs
- , Gonçalo Espregueira Themudo
- & Wesley K. Thompson
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Article
| Open AccessDiscordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy
Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder are co-occurring neurodevelopmental conditions displaying strong, discordant polygenic associations with educational attainment. Here, the authors study genetic mechanisms underlying genome-wide correlation patterns across these traits.
- Ellen Verhoef
- , Jakob Grove
- & Beate St Pourcain
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Article
| Open AccessSchizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations
Overlapping genes have been implicated in schizophrenia and neurodevelopmental disorders. Here, the authors overlap de novo variants in the two types of disorders and find variants in these genes with the same functional effect and in some cases the same specific variants.
- Elliott Rees
- , Hugo D. J. Creeth
- & Michael C. O’Donovan
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Article
| Open AccessGenome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.
- Kira A. Perzel Mandell
- , Nicholas J. Eagles
- & Andrew E. Jaffe
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Article
| Open AccessSystematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder
The significance of rare and de novo variants in bipolar disorder is not well understood. Here, the authors have analyzed whole exome/genome data from trios to identify deleterious de novo variants associated with bipolar disorder.
- Masaki Nishioka
- , An-a Kazuno
- & Atsushi Takata
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Article
| Open AccessAberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism
Restricted and repetitive behaviors (RRBs) are a core clinical feature of autism, yet the brain basis of RRBs is unknown. Here, the authors demonstrate that aberrant cognitive control and motor circuit dynamics differentially predict three distinct symptom clusters that define RRBs.
- Kaustubh Supekar
- , Srikanth Ryali
- & Vinod Menon
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Article
| Open AccessBrain network dynamics during working memory are modulated by dopamine and diminished in schizophrenia
Working memory requires the brain to switch between cognitive states and activity patterns. Here, the authors show that the steering of these neural network dynamics is influenced by dopamine D1- and D2-receptor function and altered in schizophrenia.
- Urs Braun
- , Anais Harneit
- & Heike Tost
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Article
| Open AccessThe genetic architecture of the human thalamus and its overlap with ten common brain disorders
Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
- Torbjørn Elvsåshagen
- , Alexey Shadrin
- & Tobias Kaufmann
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Article
| Open AccessDetecting local genetic correlations with scan statistics
Genetic correlation analyses give insight on complex disease, yet are limited by oversimplification. Here, the authors present LOGODetect, a method using summary statistics from genome-wide association studies to identify genomic regions with correlation signals across multiple phenotypes.
- Hanmin Guo
- , James J. Li
- & Lin Hou
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Article
| Open AccessHistamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice
Social impairment and anhedonia are common negative symptoms in patients with schizophrenia. Here, the authors show that the histamine H1 receptor in cholinergic neurons in the basal forebrain has a critical role in sensorimotor gating, social behaviour, and anhedonia-like behaviour in mice.
- Li Cheng
- , Cenglin Xu
- & Zhong Chen
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Article
| Open AccessRisk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder
ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.
- Ditte Demontis
- , Raymond K. Walters
- & Anders D. Børglum
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Article
| Open AccessEpigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR
PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.
- Alicia K. Smith
- , Andrew Ratanatharathorn
- & Caroline M. Nievergelt
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Article
| Open AccessEndocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice
Ketamine is used for sedation and treatment of depression, but is also a drug of abuse. Here the authors show that ketamine modulates the endocannabinoid system in mice, and that this may contribute to its psychoactive effects.
- Wei Xu
- , Hongchun Li
- & Xiaobo Cen
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Article
| Open AccessPCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
The role of ciliary/centriolar components in the postnatal brain is unclear. Here, the authors show via ablation of Pcm1 in mice that degenerative ciliary/centriolar phenotypes induce neuroanatomical and behavioral changes. Sequencing of PCM1 in human cohorts and zebrafish in vivo complementation suggests PCM1 mutations can contribute to schizophrenia.
- Tanner O. Monroe
- , Melanie E. Garrett
- & Nicholas Katsanis
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Article
| Open AccessA shared genetic contribution to breast cancer and schizophrenia
Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.
- Donghao Lu
- , Jie Song
- & Unnur A. Valdimarsdóttir
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Article
| Open AccessPreventing and treating PTSD-like memory by trauma contextualization
Individuals with PTSD are unable to recollect contextual cues related to the trauma. Here the authors show that this contextual amnesia, associated with the inhibition of hippocampal activity, is causally involved in PTSD-like hypermnesia in mice, and that re-exposure to all trauma-related cues eliminates PTSD-like memory while promoting normal fear memory.
- Alice Shaam Al Abed
- , Eva-Gunnel Ducourneau
- & Aline Desmedt
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Article
| Open AccessElevated rates of autism, other neurodevelopmental and psychiatric diagnoses, and autistic traits in transgender and gender-diverse individuals
It is unclear if rates of autism and other neurodevelopmental and psychiatric diagnoses are elevated in transgender and gender-diverse individuals compared to cisgender individuals. Here, the authors use data from five different large-scale datasets to identify elevated rates of autism diagnoses, diagnoses of other neurodevelopmental and psychiatric conditions, and elevated traits related to autism in transgender and gender-diverse individuals, compared to cisgender individuals.
- Varun Warrier
- , David M. Greenberg
- & Simon Baron-Cohen
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Article
| Open AccessA unified connectomic target for deep brain stimulation in obsessive-compulsive disorder
Li et al. analyzed structural connectivity of deep brain stimulation electrodes in 50 patients suffering from obsessive-compulsive disorder operated at four centers. Connectivity to a specific tract within the anterior limb of the internal capsule was associated with optimal treatment response across cohorts, surgeons and centers.
- Ningfei Li
- , Juan Carlos Baldermann
- & Andreas Horn
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Article
| Open AccessTopoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity
Topoisomerase 3β (Top3β) solves topological stress in DNA or RNA metabolism and its mutations are linked to mental disorders. Here, the authors describe transcriptional and behavioural impairments in Top3β-knockout mice and show that these are linked to impaired neurogenesis and synaptic plasticity.
- Yuyoung Joo
- , Yutong Xue
- & Weidong Wang
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Article
| Open AccessSIRT1 accelerates the progression of activity-based anorexia
Anorexia nervosa is an eating disorder characterized by fear of gaining weight that can lead to serious complications. Here the authors show that inhibition of SIRT1 is protective against the onset and progression of anorectic behavior in an activity-based anorexia model, suggesting SIRT1 could be a potential therapeutic target.
- Timothy M. Robinette
- , Justin W. Nicholatos
- & Sergiy Libert
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Article
| Open AccessWeaker neural suppression in autism
Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.
- Michael-Paul Schallmo
- , Tamar Kolodny
- & Scott O. Murray
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Article
| Open AccessA phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.
- Xueyi Shen
- , David M. Howard
- & Andrew M. McIntosh