American journal of human genetics最新文献

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

Whole-skin DNA methylation variation has been implicated in several diseases, including melanoma, but its genetic basis has not yet been fully characterized. Using bulk skin tissue samples from 414 healthy female UK twins, we performed twin-based heritability and methylation quantitative trait loci (meQTL) analyses for >400,000 DNA methylation sites. We find that the human skin DNA methylome is on average less heritable than previously estimated in blood and other tissues (mean heritability: 10.02%). meQTL analysis identified local genetic effects influencing DNA methylation at 18.8% (76,442) of tested CpG sites, as well as 1,775 CpG sites associated with at least one distal genetic variant. As a functional follow-up, we performed skin expression QTL (eQTL) analyses in a partially overlapping sample of 604 female twins. Colocalization analysis identified over 3,500 shared genetic effects affecting thousands of CpG sites (10,067) and genes (4,475). Mediation analysis of putative colocalized gene-CpG pairs identified 114 genes with evidence for eQTL effects being mediated by DNA methylation in skin, including in genes implicating skin disease such as ALOX12 and CSPG4. We further explored the relevance of skin meQTLs to skin disease and found that skin meQTLs and CpGs under genetic influence were enriched for multiple skin-related genome-wide and epigenome-wide association signals, including for melanoma and psoriasis. Our findings give insights into the regulatory landscape of epigenomic variation in skin.

Regulation of gene expression is a vital component of neurological homeostasis. Cataloging the consequences of endogenous gene expression on the physical structure and connectivity of the brain offers a means of unifying trait-associated genetic variation with trait-associated neurological features. We perform tissue-specific transcriptome-wide association studies (TWASs) on over 3,400 neuroimaging phenotypes in the UK Biobank (N = 33,224) using our joint-tissue imputation (JTI)-TWAS method. We identify highly significant associations between predicted expression for 7,192 genes and a wide variety of measures of the brain derived from magnetic resonance imaging (MRI). Our approach generates reproducible results in internal and external replication datasets. Genetically determined expression alone is sufficient for high-fidelity reconstruction of brain structure and organization. We demonstrate complementary benefits of cross-tissue and single-tissue analyses toward an integrated neurobiology and provide evidence that gene expression outside the central nervous system provides unique insights into brain health. As an application, we provide evidence suggesting that the genetically regulated expression of schizophrenia risk genes causally affects over 73% of neurological phenotypes that are altered in individuals with schizophrenia (as identified by neuroimaging studies). Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. By linking neuroimaging-derived phenotypes with expression levels of specific genes, this resource represents a powerful gene prioritization schema that can improve our understanding of brain function, development, and disease. The use of multiple different cortical and subcortical atlases in the resource facilitates direct integration of these data with findings from a diverse range of clinical neuroimaging studies.

A health workforce capable of implementing genomic medicine requires effective genomics education. Genomics education interventions developed for health professions over the last two decades, and their impact, are variably described in the literature. To inform an evaluation framework for genomics education, we undertook an exploratory scoping review of published needs assessments for, and/or evaluations of, genomics education interventions for health professionals from 2000 to 2023. We retrieved and screened 4,659 records across the two searches with 363 being selected for full-text review and consideration by an interdisciplinary working group. 104 articles were selected for inclusion in the review-60 needs assessments, 52 genomics education evaluations, and eight describing both. Included articles spanned all years and described education interventions in over 30 countries. Target audiences included medical specialists, nurses/midwives, and/or allied health professionals. Evaluation questions, outcomes, and measures were extracted, categorized, and tabulated to iteratively compare measures across stages of genomics education evaluation: planning (pre-implementation), development and delivery (implementation), and impact (immediate, intermediate, or long-term outcomes). They are presented here along with descriptions of study designs. We document the wide variability in evaluation approaches and terminology used to define measures and note that few articles considered downstream (long-term) outcomes of genomics education interventions. Alongside the evaluation framework for genomics education, results from this scoping review form part of a toolkit to help educators to undertake rigorous genomics evaluation that is fit for purpose and can contribute to the growing evidence base of the contribution of genomics education in implementation strategies for genomic medicine.

In Mendelian randomization, two single SNP-trait correlation-based methods have been developed to infer the causal direction between an exposure (e.g., a gene) and an outcome (e.g., a trait), called MR Steiger's method and its recent extension called Causal Direction-Ratio (CD-Ratio). Here we propose an approach based on R², the coefficient of determination, to combine information from multiple (possibly correlated) SNPs to simultaneously infer the presence and direction of a causal relationship between an exposure and an outcome. Our proposed method generalizes Steiger's method from using a single SNP to multiple SNPs as IVs. It is especially useful in transcriptome-wide association studies (TWASs) (and similar applications) with typically small sample sizes for gene expression (or another molecular trait) data, providing a more flexible and powerful approach to inferring causal directions. It can be applied to GWAS summary data with a reference panel. We also discuss the influence of invalid IVs and introduce a new approach called R2S to select and remove invalid IVs (if any) to enhance the robustness. We compared the performance of the proposed method with existing methods in simulations to demonstrate its advantages. We applied the methods to identify causal genes for high/low-density lipoprotein cholesterol (HDL/LDL) using the individual-level GTEx gene expression data and UK Biobank GWAS data. The proposed method was able to confirm some well-known causal genes while identifying some novel ones. Additionally, we illustrated an application of the proposed method to GWAS summary to infer causal relationships between HDL/LDL and stroke/coronary artery disease (CAD).

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.