Publications by authors named "Patrick F Sullivan"

367 Publications

Psychiatric Genetics Before "Genetics".

Am J Psychiatry 2021 06;178(6):475-476

University of North Carolina, Departments of Genetics and Psychiatry, Chapel Hill; Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm.

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http://dx.doi.org/10.1176/appi.ajp.2021.21020136DOI Listing
June 2021

The epidemiology of psychiatric disorders in Africa: a scoping review.

Lancet Psychiatry 2021 08 8;8(8):717-731. Epub 2021 Jun 8.

Division of Translational Epidemiology, Department of Psychiatry, New York State Psychiatric Institute, New York, NY, USA; Columbia University Vagelos College of Physicians and Surgeons; New York State Psychiatric Institute, New York, NY, USA. Electronic address:

This scoping review of population-based epidemiological studies was done to provide background information on the prevalences and distribution of psychiatric disorders in Africa for calls to broaden diversity in psychiatric genetic studies. We searched PubMed, EMBASE, and Web of Science to retrieve relevant literature in English, French, and Portuguese from Jan 1, 1984, to Aug 18, 2020. In 36 studies from 12 African countries, the lifetime prevalence ranged from 3·3% to 9·8% for mood disorders, from 5·7% to 15·8% for anxiety disorders, from 3·7% to 13·3% for substance use disorders, and from 1·0% to 4·4% for psychotic disorders. Although the prevalence of mood and anxiety disorders appears to be lower than that observed in research outside the continent, we identified similar distributions by gender, although not by age or urbanicity. This review reveals gaps in epidemiological research on psychiatric disorders and opportunities to leverage existing epidemiological and genetic research within Africa to advance our understanding of psychiatric disorders. Studies that are methodologically comparable but diverse in geographical context are needed to advance psychiatric epidemiology and provide a foundation for understanding environmental risk in genetic studies of diverse populations globally.
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http://dx.doi.org/10.1016/S2215-0366(21)00009-2DOI Listing
August 2021

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

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

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), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) 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.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Editorial overview: Rare CNV disorders and neuropsychiatric phenotypes: opportunities, challenges, solutions.

Curr Opin Genet Dev 2021 Jun 28;68:iii-ix. Epub 2021 May 28.

Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.gde.2021.05.002DOI Listing
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia.

Schizophr Bull 2021 May 14. Epub 2021 May 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.
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http://dx.doi.org/10.1093/schbul/sbab052DOI Listing
May 2021

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BMC Psychiatry 2021 05 4;21(1):234. Epub 2021 May 4.

QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Herston, QLD, 4029, Australia.

Background: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder.

Methods: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED).

Discussion: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights.

Trial Registration: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .
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http://dx.doi.org/10.1186/s12888-021-03212-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097919PMC
May 2021

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

Transl Psychiatry 2021 04 12;11(1):214. Epub 2021 Apr 12.

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm and 1500/mm were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
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http://dx.doi.org/10.1038/s41398-021-01322-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042025PMC
April 2021

The association between family history and genomic burden with schizophrenia mortality: a Swedish population-based register and genetic sample study.

Transl Psychiatry 2021 03 15;11(1):163. Epub 2021 Mar 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Individuals with schizophrenia (SCZ) have a 2-3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26-2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ.
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http://dx.doi.org/10.1038/s41398-021-01282-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960991PMC
March 2021

Swedish large-scale schizophrenia study: Why do patients and healthy controls participate?

Schizophr Res 2021 02 3;228:360-366. Epub 2021 Feb 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden. Electronic address:

Insights into determination of study participation are useful for researchers, clinicians and for ethical considerations. Few large-scale genomic studies have involved motives for enrollment, in schizophrenia patients and unaffected controls. In a case-control study with participants recruited nation-wide in Sweden between 2005 and 2010, semi-structured interviews on motives and attitudes towards future studies were explored in 2767 schizophrenia cases and 4466 controls. In qualitative and quantitative analyses, we identified altruism as a major determinant in 84% of the cases and in 97% of the controls. Among pre-defined subcategories of altruism, cases with schizophrenia were more often referring to science for example, 'I want to help science move forward' or 'I want better medications for future generations' in relation to unaffected controls that were more often referring to common humanity such as 'It is my duty and responsibility to help'. In schizophrenia, motives related to personal benefit and social influence were reported by 9% and 5%. We conclude that individuals with schizophrenia frequently report altruistic motives for study participation, almost to the same extent as unaffected controls. In contrast to unfortunate stereotypes, people with schizophrenia wish others to benefit from their experiences with severe mental illness and should not be refrained from participating in genomic research.
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http://dx.doi.org/10.1016/j.schres.2021.01.007DOI Listing
February 2021

Herbivory and warming interact in opposing patterns of covariation between arctic shrub species at large and local scales.

Proc Natl Acad Sci U S A 2021 02;118(6)

Environment and Natural Resources Institute, University of Alaska Anchorage, Anchorage, AK 99508.

A major challenge in predicting species' distributional responses to climate change involves resolving interactions between abiotic and biotic factors in structuring ecological communities. This challenge reflects the classical conceptualization of species' regional distributions as simultaneously constrained by climatic conditions, while by necessity emerging from local biotic interactions. A ubiquitous pattern in nature illustrates this dichotomy: potentially competing species covary positively at large scales but negatively at local scales. Recent theory poses a resolution to this conundrum by predicting roles of both abiotic and biotic factors in covariation of species at both scales, but empirical tests have lagged such developments. We conducted a 15-y warming and herbivore-exclusion experiment to investigate drivers of opposing patterns of covariation between two codominant arctic shrub species at large and local scales. Climatic conditions and biotic exploitation mediated both positive covariation between these species at the landscape scale and negative covariation between them locally. Furthermore, covariation between the two species conferred resilience in ecosystem carbon uptake. This study thus lends empirical support to developing theoretical solutions to a long-standing ecological puzzle, while highlighting its relevance to understanding community compositional responses to climate change.
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http://dx.doi.org/10.1073/pnas.2015158118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017923PMC
February 2021

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Mol Psychiatry 2021 Jan 22. Epub 2021 Jan 22.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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http://dx.doi.org/10.1038/s41380-020-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295400PMC
January 2021

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy.

Mol Psychiatry 2021 Jan 22. Epub 2021 Jan 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
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http://dx.doi.org/10.1038/s41380-020-00984-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295407PMC
January 2021

The state of the science in psychiatric genomics.

Psychol Med 2021 Jan 12:1-3. Epub 2021 Jan 12.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

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http://dx.doi.org/10.1017/S0033291720004900DOI Listing
January 2021

Divergence of Arctic shrub growth associated with sea ice decline.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33334-33344. Epub 2020 Dec 14.

Department of Ecology and Genetics, University of Oulu and UArctic, 90570 Oulu, Finland.

Arctic sea ice extent (SIE) is declining at an accelerating rate with a wide range of ecological consequences. However, determining sea ice effects on tundra vegetation remains a challenge. In this study, we examined the universality or lack thereof in tundra shrub growth responses to changes in SIE and summer climate across the Pan-Arctic, taking advantage of 23 tundra shrub-ring chronologies from 19 widely distributed sites (56°N to 83°N). We show a clear divergence in shrub growth responses to SIE that began in the mid-1990s, with 39% of the chronologies showing declines and 57% showing increases in radial growth (decreasers and increasers, respectively). Structural equation models revealed that declining SIE was associated with rising air temperature and precipitation for increasers and with increasingly dry conditions for decreasers. Decreasers tended to be from areas of the Arctic with lower summer precipitation and their growth decline was related to decreases in the standardized precipitation evapotranspiration index. Our findings suggest that moisture limitation, associated with declining SIE, might inhibit the positive effects of warming on shrub growth over a considerable part of the terrestrial Arctic, thereby complicating predictions of vegetation change and future tundra productivity.
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http://dx.doi.org/10.1073/pnas.2013311117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776857PMC
December 2020

PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.

Nat Commun 2020 11 19;11(1):5903. Epub 2020 Nov 19.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.
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http://dx.doi.org/10.1038/s41467-020-19637-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677393PMC
November 2020

Treatment-resistant psychotic symptoms and early-onset dementia: A case report of the 3q29 deletion syndrome.

Schizophr Res 2020 10 14;224:195-197. Epub 2020 Sep 14.

Translational Neuroscience LLC, Conshohocken, PA, USA. Electronic address:

The 3q29 deletion is a rare copy number variant associated with neurodevelopmental and psychiatric disorders, including a >40-fold increased risk for schizophrenia. Current understanding of the clinical phenotype is derived primarily from published cases of patients in childhood or early adolescence. Symptoms include mild to moderate learning disability, developmental delay, facial dysmorphism, microcephaly, ocular disorders, and gastrointestinal abnormalities. There is, however, a lack of detailed longitudinal case studies describing 3q29 deletion syndrome in adults with psychosis. In this case report, we describe the lifetime clinical portrait of a 57-year-old woman with 3q29 deletion syndrome, treatment-resistant psychotic symptoms, multiple medical comorbidities, and a previously unreported co-occurrence of early-onset dementia.
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http://dx.doi.org/10.1016/j.schres.2020.08.012DOI Listing
October 2020

Labile carbon limits late winter microbial activity near Arctic treeline.

Nat Commun 2020 08 12;11(1):4024. Epub 2020 Aug 12.

Department of Environmental Sciences, University of Toledo, Toledo, OH, 43606, USA.

Soil microbial communities remain active during much of the Arctic winter, despite deeply frozen soils. Overwinter microbial activity affects the global carbon (C) budget, nutrient cycling, and vegetation composition. Microbial respiration is highly temperature sensitive in frozen soils, as liquid water and solute availability decrease rapidly with declining temperature. Climate warming and changes in snowpack are leading to warmer Arctic winter soils. Warmer winter soils are thought to yield greater microbial respiration of available C, greater overwinter CO efflux and greater nutrient availability to plants at thaw. Using field and laboratory observations and experiments, we demonstrate that persistently warm winter soils can lead to labile C starvation and reduced microbial respiration, despite the high C content of most Arctic soils. If winter soils continue to warm, microbial C limitation will reduce expected CO emissions and alter soil nutrient cycling, if not countered by greater labile C inputs.
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http://dx.doi.org/10.1038/s41467-020-17790-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423931PMC
August 2020

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX).

G3 (Bethesda) 2020 09 2;10(9):3165-3177. Epub 2020 Sep 2.

Department of Genetics, University of North Carolina, Chapel Hill, NC

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated ( < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.
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http://dx.doi.org/10.1534/g3.120.400975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466989PMC
September 2020

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

Am J Med Genet B Neuropsychiatr Genet 2020 09 18;183(6):309-330. Epub 2020 Jul 18.

Max Planck Institute of Psychiatry, Munich, Germany.

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.
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http://dx.doi.org/10.1002/ajmg.b.32807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991693PMC
September 2020

Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases.

Mol Cell 2020 08 26;79(3):521-534.e15. Epub 2020 Jun 26.

Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Computer and Data Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
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http://dx.doi.org/10.1016/j.molcel.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415676PMC
August 2020

Chronicity and Sex Affect Genetic Risk Prediction in Schizophrenia.

Front Psychiatry 2020 9;11:313. Epub 2020 Jun 9.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Schizophrenia (SCZ) is a severe mental disorder with immense personal and societal costs; identifying individuals at risk is therefore of utmost importance. Genomic risk profile scores (GRPS) have been shown to significantly predict cases-control status. Making use of a large-population based sample from Sweden, we replicate a previous finding demonstrating that the GRPS is strongly associated with admission frequency and chronicity of SCZ. Furthermore, we were able to show a substantial gap in prediction accuracy between males and females. In sum, our results indicate that prediction accuracy by GRPS depends on clinical and demographic characteristics.
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http://dx.doi.org/10.3389/fpsyt.2020.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297201PMC
June 2020

mTADA is a framework for identifying risk genes from de novo mutations in multiple traits.

Nat Commun 2020 06 10;11(1):2929. Epub 2020 Jun 10.

Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Joint analysis of multiple traits can result in the identification of associations not found through the analysis of each trait in isolation. Studies of neuropsychiatric disorders and congenital heart disease (CHD) which use de novo mutations (DNMs) from parent-offspring trios have reported multiple putatively causal genes. However, a joint analysis method designed to integrate DNMs from multiple studies has yet to be implemented. We here introduce multiple-trait TADA (mTADA) which jointly analyzes two traits using DNMs from non-overlapping family samples. We first demonstrate that mTADA is able to leverage genetic overlaps to increase the statistical power of risk-gene identification. We then apply mTADA to large datasets of >13,000 trios for five neuropsychiatric disorders and CHD. We report additional risk genes for schizophrenia, epileptic encephalopathies and CHD. We outline some shared and specific biological information of intellectual disability and CHD by conducting systems biology analyses of genes prioritized by mTADA.
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http://dx.doi.org/10.1038/s41467-020-16487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287090PMC
June 2020

The effect of LRRK2 loss-of-function variants in humans.

Nat Med 2020 06 27;26(6):869-877. Epub 2020 May 27.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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http://dx.doi.org/10.1038/s41591-020-0893-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303015PMC
June 2020

Genetic stratification of depression in UK Biobank.

Transl Psychiatry 2020 05 24;10(1):163. Epub 2020 May 24.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup.
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http://dx.doi.org/10.1038/s41398-020-0848-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246256PMC
May 2020

Test-statistic inflation in methylome-wide association studies.

Epigenetics 2020 11 19;15(11):1163-1166. Epub 2020 May 19.

Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University , Richmond, VA, USA.

Recent years have seen a surge of methylome-wide association studies (MWAS). We observed that many of these studies suffer from test statistic inflation that is most likely caused by commonly used quality control (QC) pipelines not going far enough to remove technical artefacts. To support this claim, we reanalysed GEO datasets with an improved QC pipeline that reduced test-statistic inflation parameter lambda from the original mean/median of 20.16/15.17 to 3.07/1.14. Furthermore, the mean/median number of methylome-wide significant findings was reduced by 65,688/57,805 loci after more thorough QC. To avoid such false positives we argue for more extensive QC and that reporting the test-statistic inflation parameter lambda become standard for all MWAS allowing readers to better assess the risk of false discoveries.
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http://dx.doi.org/10.1080/15592294.2020.1758382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595582PMC
November 2020

Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders.

Mol Psychiatry 2020 May 12. Epub 2020 May 12.

Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium-schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
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http://dx.doi.org/10.1038/s41380-020-0705-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657979PMC
May 2020
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