Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

American Journal of Psychiatry, Год журнала: 2022, Номер 179(11), С. 833 - 843

Опубликована: Сен. 7, 2022

Objective: Mental disorders are heritable and polygenic, genome-wide genetic correlations (rg) have indicated widespread shared risk across multiple related traits, mirroring their overlapping clinical characteristics. However, rg may underestimate the underpinnings of mental traits because it does not differentiate mixtures concordant discordant effects from an absence overlap. Using novel statistical genetics tools, authors aimed to evaluate overlap between when accounting for mixed effect directions. Methods: The applied bivariate causal mixture model (MiXeR) summary statistics four disorders, height association studies (Ns ranged 53,293 766,345). MiXeR estimated number “causal” variants a given trait (“polygenicity”), correlation (rgs). Local was investigated using LAVA. Results: Among ADHD least polygenic (5.6K variants), followed by bipolar disorder (8.6K), schizophrenia (9.6K), depression (14.5K). Most were (4.4K–9.3K) (5.2K–12.8K), but with disorder-specific variations in rgs. Overlap small (0.7K–1.1K). estimates correlated LAVA local (r=0.88, p<0.001). Conclusions: There is extensive directions few variants. This suggests that predominantly differentiated divergent distributions pleiotropic rather than represents conceptual advance our understanding landscape architecture which inform discovery, biological characterization, nosology, prediction.

Язык: Английский

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Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets

Neuropsychopharmacology, Год журнала: 2024, Номер 49(6), С. 1033 - 1041

Опубликована: Фев. 24, 2024

Язык: Английский

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The shared genetic risk architecture of neurological and psychiatric disorders: a genome-wide analysis

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 23, 2023

While neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathobiological mechanisms. However, the extent which these heritable share genetic influences remains unclear. Here, we performed a comprehensive analysis of GWAS data, involving nearly 1 million cases across ten diseases disorders, compare their common risk biological underpinnings. Using complementary statistical tools, demonstrate widespread overlap even in absence correlations. This indicates that large set variants impact multiple but with divergent effect sizes. Furthermore, interrogation revealed range processes associated diseases, while consistently implicated neuronal biology. Altogether, study key etiological aspects, has important implications for disease classification, precision medicine, clinical practice.

Язык: Английский

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Genetic overlap between schizophrenia and cognitive performance

Schizophrenia, Год журнала: 2024, Номер 10(1)

Опубликована: Март 5, 2024

Abstract Schizophrenia (SCZ), a highly heritable mental disorder, is characterized by cognitive impairment, yet the extent of shared genetic basis between schizophrenia and performance (CP) remains poorly understood. Therefore, we aimed to explore polygenic overlap SCZ CP. Specifically, bivariate causal mixture model (MiXeR) was employed estimate ( n = 130,644) CP 257,841), conjunctional false discovery rate (conjFDR) approach used identify loci. Subsequently, functional annotation enrichment analysis were carried out on identified genomic The MiXeR analyses revealed that 9.6 K variants are associated with 10.9 for CP, which 9.5 these two traits (Dice coefficient 92.8%). By employing conjFDR, 236 loci jointly 139 novel traits. Within loci, 60 exhibited consistent effect directions, while 176 had opposite directions. Functional indicated mainly located in intronic intergenic regions, found be involved relevant biological processes such as nervous system development, multicellular organism generation neurons. Together, our findings provide insights into architecture suggesting common pathways mechanisms contributing both

Язык: Английский

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Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 26, 2024

Abstract Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of modalities could inform us on the integration function, micro- and macrostructure. Here we show extensive genetic overlap at a locus gene level in UK Biobank ( N = 34,029) ABCD Study 8607). When jointly analysing phenotypes MRI genome-wide association study (GWAS) with Multivariate Omnibus Statistical Test (MOSTest), boost discovery loci genes beyond previously identified effects for each individually. Cross-modality are involved fundamental biological processes predominantly expressed during prenatal development. We additionally prediction psychiatric disorders by conditioning independent GWAS our multimodal multivariate GWAS. These findings shed light shared mechanisms underlying variation morphology, connectivity, tissue composition.

Язык: Английский

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The Genetic Specificity of Cognitive Tests After Controlling for General Cognitive Ability

Behavior Genetics, Год журнала: 2025, Номер 55(2), С. 103 - 113

Опубликована: Фев. 18, 2025

Diverse tests of cognitive abilities correlate about 0.30 phenotypically and 0.60 genetically. Their phenotypic overlap defines general ability (g), driven largely by genetic overlap. Consequently, much our understanding the landscape specific likely reflects g rather than themselves. Removing this g-associated variance will sharpen research on tests. Here, we use Genomic Structural Equation Modelling (Genomic SEM) to remove shared among 12 diverse that capture verbal nonverbal domains. We applied SEM summary statistics from largest genome-wide association studies (GenLang Consortium, five tests) (UK Biobank, seven chart independent as compared uncorrected found SNP heritabilities were nearly high for corrected uncorrected: average heritability was 0.16 (SE = 0.02) 0.13 g. Despite this, transformed after controlling genomic The matrix positive correlations (average 0.45) disappeared g-correction, some strong negative emerged; instance, Memory Word (-0.72), Fluid Symbol Tower Spelling (-0.79). these g-corrected can be used researchers create polygenic scores focus specificity

Язык: Английский

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Identification of ethanol analgesia quantitative trait loci and candidate genes in BXD recombinant inbred mouse lines

Addiction Biology, Год журнала: 2025, Номер 30(2)

Опубликована: Фев. 1, 2025

Alcohol consumption produces acute analgesic effects, and people experiencing pain conditions may drink alcohol to alleviate discomfort. However, tolerance the properties of could prompt escalating dependence. Both nociception alcohol-induced analgesia are under significant genetic control. Understanding architecture these processes inform better treatment options for with conditions. This study aims identify quantitative trait loci (QTL) driving variation in ethanol-induced across BXD recombinant inbred mouse lines. Male female mice from 62 strains received ethanol or saline oral gavage five days were tested hot plate (HP) latency at baseline, Day 1 5. QTL mapping HP phenotypes identified a provisional on chromosome 17 receiving ethanol. An additional highly suggestive was present 9 difference pre- post-ethanol thermal nociception. Candidate genes within support intervals provisionally using phenotypic correlations transcriptomic database, expression analysis other bioinformatics inquiries. The combined behavioural bioinformatic analyses yielded strong candidate genes, specifically Myo6. Thus, results this contribute significantly our understanding molecular basis individual response

Язык: Английский

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Investigating the shared genetic architecture between schizophrenia and sex hormone traits

Translational Psychiatry, Год журнала: 2025, Номер 15(1)

Опубликована: Март 17, 2025

Sex hormones are involved in schizophrenia pathogenesis; however, their direction and genetic overlap remain unknown. By leveraging summary statistics from large-scale genome-wide association studies, we quantified the shared architecture between four sex hormone traits. Linkage disequilibrium score regression bivariate causal mixture modeling strategies showed significant positive correlations hormone-binding globulin (SHBG), total testosterone, schizophrenia, while bioavailable testosterone were negatively correlated. Estradiol a weak correlation with little polygenic overlap. The conjunctional false discovery rate method identified 303 lead single-nucleotide polymorphisms (SNPs) jointly genomic loci SHBG, 130, 52, 9 SNPs estradiol, respectively. Functional annotation suggests that mitotic sister chromatid segregation N-glycan biosynthesis may be common mechanisms underlying regulation onset. In conclusion, this study clarified inherent relationships traits, highlighted roles of pathogenesis delivered potential targets for further validation.

Язык: Английский

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Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 5, 2024

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% these EOAD cases remain unexplained by pathogenic mutations. Using data from and controls, we performed genome-wide association study (GWAS) trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six the ancestry-specific analyses two analysis. By integrating gene-based analysis, eQTL, pQTL functional annotations, nominate four genes are involved microglia activation, glutamate production, signaling pathways. These results indicate EOAD, although sharing many LOAD, harbors unique pathways could be used to create better prediction models or target identification for this type AD

Язык: Английский

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Human‐specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders

Genes Brain & Behavior, Год журнала: 2024, Номер 23(3)

Опубликована: Май 16, 2024

Abstract Reading disorders (RD) are human‐specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome‐wide association study (GWAS) have been identified that jointly provided little clues pathophysiology. Leveraging genomic information, we critically assessed the RD candidates for first time found substantial features within. The GWAS (i.e., population signals) were distinct familial counterparts more likely pleiotropic neuropsychiatric traits to harbor regulatory elements (HSREs). Candidate human cortical morphology indeed showed expression adult brain cortices, particularly neuroglia regulated by HSREs. Expression levels across developmental stages clear pattern uplifted early development crucial development. Following new insights cognitive traits, four novel sub‐significant associations FOXO3 , MAPT KMT2E HTT ) Semaphorin gene family functional priors SEMA3A SEMA3E SEMA5B ). These related neuronal plasticity disorders, mostly conserved had evident neuroglial cells. Our findings illuminated regulation—an emerging hotspot studying neurodevelopmental highlighted need improving phenotyping avoid jeopardizing future genetic studies RD.

Язык: Английский

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