Familial confounding in the associations between maternal health and autism

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Evidence suggests that maternal health in pregnancy is associated with autism the offspring. However, most diagnoses pregnant women have not been examined, and role of familial confounding remains unknown. Our cohort included all children born Denmark between 1998 2015 (n = 1,131,899) their parents. We fitted Cox proportional hazard regression models to estimate likelihood each prenatal ICD-10 diagnosis, accounting for disease chronicity comorbidity, correlations sociodemographic factors. examined evidence using discordant sibling paternal negative control designs. Among 1,131,899 individuals our sample, 18,374 (1.6%) were diagnosed by end follow-up. Across 236 we tested (prevalence ≥0.1%), 30 significantly after factors, disorder correction multiple testing. This obstetric, cardiometabolic psychiatric disorders (for example, diabetes (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.31) depression (HR 1.49, CI 1.27-1.75)), previously shown be autism. Family-based analyses provided strong observed associations. findings indicate pervasive associations offspring underscore these are largely attributable confounding.

Language: Английский

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Unveiling genetic substrates of brain–heart comorbidities: Integration of both common and rare variants

The Innovation Life, Journal Year: 2025, Volume and Issue: unknown, P. 100118 - 100118

Published: Jan. 1, 2025

Language: Английский

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Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS revealed the as significant contributor to disease. However, prioritizing causal common and rare human disease, understanding how selective pressures have shaped genome, remains challenge. Here, we predicted effects of 15 million with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts adult fetal brain heart, producing nearly two context-specific predictions. Using these predictions, distinguish candidate underlying traits diseases their effects. While variant are more cell-type-specific, exert cell-type-shared regulatory effects, particularly targeting affecting neurons. To prioritize de novo mutations extreme developed FLARE, functional genomic model constraint. FLARE outperformed other methods case from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate potential integrating maps population genetics learning-based effect prediction elucidate mechanisms development disease–ultimately, supporting notion genetic contributions neurodevelopmental disorders predominantly rare.

Language: Английский

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Common Genetic Variants Modify Disease Risk and Clinical Presentation in Monogenic Diabetes

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Abstract The contribution of polygenic background in young onset monogenic disorders needs further exploration. Understanding this will provide new biological insights and may improve risk prediction disease. Here we investigated the role MODY—a common disorder with an age-dependent onset.We found strong enrichment type 2 diabetes (T2D) risk, but not 1 genetically confirmed MODY cases. This T2D burden, primarily through beta-cell dysfunction pathways, was strongly associated earlier age diagnosis increased severity. Common genetic variants collectively accounted for 24% (p<0.0001) phenotypic variability. Using a large population cohort, demonstrated that burden substantially modifies individuals pathogenic variants, ranging from 11% to 81%. Finally, show MODY-like phenotypes without causal variant had elevated related traits representing potential phenocopies. These findings reveal substantial influence variation shaping clinical presentation early-onset disorders. Incorporating these estimates carrying variants.

Language: Английский

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Rapidly evolved genomic regions shape individual language abilities in present-day humans

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

1 Summary Minor genetic changes have produced profound differences in cognitive abilities between humans and our closest relatives, particularly language. Despite decades of research, ranging from single-gene studies to broader evolutionary analyses[1, 2, 3, 4, 5], key questions about the genomic foundations human language persisted, including which sequences are involved, how they evolved, whether similar occur other vocal learning species. Here we provide first evidence directly linking rapidly evolved regions contemporary humans. Through extensive analysis 65 million years events over 30,000 individuals, demonstrate that Human Ancestor Quickly Evolved Regions (HAQERs)[5] - accumulated mutations after human-chimpanzee split specifically influence but not general cognition. These shape development by altering binding Forkhead domain transcription factors, FOXP2 . Strikingly, language-associated HAQER variants show higher prevalence Neanderthals than modern humans, been stable throughout recent history, convergent evolution across mammalian learners. An unexpected pattern balancing selection acting on these apparently beneficial alleles is explained their pleiotropic effects prenatal brain contributing birth complications, reflecting an trade-off capability reproductive fitness. By developing Evolution Stratified-Polygenic Score analysis, capabilities likely emerged before human-Neanderthal far earlier previously thought[3, 6, 7]. Our findings establish direct link ancient divergence present-day variation abilities, while revealing constraints continue development.

Language: Английский

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Intergenerational transmission of polygenic predisposition for neuropsychiatric traits on emotional and behavioural difficulties in childhood

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 18, 2025

Abstract Childhood emotional and behavioural difficulties tend to co-occur often precede diagnosed neuropsychiatric conditions. Identifying shared specific risk factors for early-life mental health is therefore essential prevention strategies. Here, we examine how parental shape their offspring’s symptoms (e.g. feelings of anxiety, restlessness) using data from 14,959 genotyped family trios the Norwegian Mother, Father Child Cohort Study (MoBa). We model maternal reports symptoms, organizing them into general domains. then investigate direct (genetically transmitted) indirect (environmentally mediated) contributions polygenic neuropsychiatric-related traits whether these are across symptoms. observe evidence consistent with an environmental route symptomatology beyond genetic transmission, while also demonstrating domain-specific contributions. These findings improve our understanding early pathways that can be targeted in preventive interventions aiming interrupt intergenerational cycle transmission.

Language: Английский

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Pharmacogenomic and Pharmacomicrobiomic Aspects of Drugs of Abuse

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 403 - 403

Published: March 30, 2025

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to pharmacotherapy various drugs abuse, including alcohol, cocaine, and opioids, identify genetic variants that contribute variability substance use disorder treatment outcomes. In addition, it explores pharmacomicrobiomic aspects use, highlighting impact gut microbiome on bioavailability, drug metabolism, pharmacodynamics, pharmacokinetics. Results: Research pharmacogenetics has identified several promising may existing pharmacotherapies for addiction. However, interpretation these findings remains limited. It is estimated factors account 20–95% responses. Therefore, alone cannot fully explain differences responses, such as diversity also play a significant role. Drug microbial biotransformation produced by exoenzymes convert low molecular weight organic compounds into analogous oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or introduction heteroatoms. Despite advances pharmacomicrobiomics, challenges persist lack standardized methodologies, inter-individual variability, limited understanding mechanisms, need large-scale validation studies develop microbiota-based biomarkers clinical use. Conclusions: Progress disorders provided biological insights pharmacological needs associated with common drug-metabolizing enzymes. The its metabolites pivotal stages addiction seeking, reward, biotransformation. integrating pharmacomicrobiomics will form crucial foundation precision personalized medicine.

Language: Английский

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Genetically Transitional Disease and the Road to Personalized Medicine

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 401 - 401

Published: March 30, 2025

Genetically transitional disease (GTD) is emerging as a new concept in genomic medicine to straddle between the traditional binary classification of monogenic and polygenic disease. Genetic testing result reports molecular laboratories have been predicated on model, which focuses pathogenic likely variants. While variants uncertain significance (VUS) are reported by laboratories, there challenges with regard their clinical application so that these often dismissed ordering physicians. Unlike Mendelian disorders, where genetic high penetrance highly probabilistic, GTD employed highlight impact low-to-moderate effect gene whose influence modified background. The may explain health conditions associated necessary but not sufficient for pathogenesis, lying mid gray zone diseases. Although VUSs reach level pathogenicity based American College Medical Genetics Genomics guidelines, they could be provisionally classified GTD-associated annotate interpret relationship VUS human appropriate implementation patient care research focusing attention individual variability responses various

Language: Английский

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Common genetic variants contribute more to rare diseases than previously thought

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Language: Английский

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Genome folding; organelle changes; self-injury

The Transmitter, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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