American journal of human genetics最新文献

Interpretation of genetic variants is most accurate when gene- and disease-specific considerations are considered. The 2015 ACMG/AMP guidelines form the basis for the application of variant interpretation criteria for Mendelian disorders. The Hereditary Breast, Ovarian, and Pancreatic Cancer Variant Curation Expert Panel (HBOP VCEP) has undertaken the process for creating gene- and disease-specific specifications for the interpretation of PALB2 germline sequence variants. The HBOP VCEP is comprised of experts in the fields of clinical and molecular genetics, epidemiology, functional assays, and variant interpretation. The group met regularly to consider each of the codes from the 2015 ACMG/AMP guidelines to determine their relevance for PALB2. After criteria were created using database analysis, literature review, and expert opinion, they were vetted against a diverse set of pilot variants and ultimately finalized. The HBOP VCEP advised against using 13 codes, limited the use of six codes, and tailored nine codes to create the final PALB2 variant interpretation guidelines. Among the 39 pilot variants, 37 were in ClinVar, and using the new specifications concordant classifications resulted for 31 of the variants (84%). Of the 14 variants of uncertain significance/conflicting variants in ClinVar, four were classified by the VCEP, likely due to code combination modifications and refined population frequency cutoffs. The PALB2-specific guidelines put forward by the HBOP VCEP represent a conservative approach to classifying variants in PALB2 and lead to improved classifications relative to current ClinVar entries. Adoption of these specifications will help to harmonize classifications deposited in the public domain.

The increasing availability of diverse biobanks has enabled multi-ancestry genome-wide association studies (GWASs) to enhance the discovery of genetic variants across traits and diseases. However, the choice of an optimal method remains debated, due to challenges in statistical power differences across ancestral groups and approaches to account for population structure. Two primary strategies exist: (1) pooled analysis, which combines individuals from all genetic backgrounds into a single dataset while adjusting for population stratification using principal components, increasing the sample size and statistical power but requiring careful control of population stratification; and (2) meta-analysis, which performs ancestry-group-specific GWASs and subsequently combines summary statistics, potentially capturing fine-scale population structure but facing limitations in handling admixed individuals. Using large-scale simulations with varying sample sizes and ancestry compositions, we compare these methods alongside real data analyses of eight continuous and five binary traits from the UK Biobank (N ≈ 324,000) and the All of Us Research Program (N ≈ 207,000). Our results demonstrate that pooled analysis generally exhibits better statistical power while effectively adjusting for population stratification. We further present a theoretical framework linking power differences to allele-frequency variations across populations. These findings, validated across both biobanks, highlight pooled analysis as a powerful and scalable strategy for multi-ancestry GWASs, improving genetic discovery while maintaining rigorous population structure control.

Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C experiments identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin three-dimensional (3D) interactions in SMS hiPSCs and 3D cortical organoids. Single-nucleus RNA sequencing of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell-cycle processes, and neuronal signaling. SMS cortical organoids displayed reduced growth, enlarged ventricles, impaired cell-cycle progression, and accelerated neuronal maturation. Through the use of a complementary hiPSC-derived 2D cortical neuronal model, we report that SMS cortical neurons exhibited accelerated dendritic growth, followed by neuronal hyperexcitability associated with reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell-cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.

Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare-variant (minor allele frequency <1%) association testing using exome-sequencing data from 402,375 participants of European ancestry in the UK Biobank for nine overall and tissue-specific fat distribution traits, we identified 19 genes where putatively damaging rare variation associated with at least one trait (Bonferroni-adjusted p < 1.58 × 10^-7) and 50 additional genes at false discovery rate (FDR) ≤1% (p ≤ 4.37 × 10^-5). These 69 genes exhibited significantly higher (one-sided t test p = 3.58 × 10^-18) common-variant prioritization scores for association with body mass index (BMI), waist-to-hip ratio adjusted for BMI, and body fat percentage than genes not significantly enriched for rare putatively damaging variation, with evidence of monotonic allelic series (dose-response relationships) among ultra-rare variants (minor allele count ≤10) in 22 genes. Combining rare and common variation evidence, allelic series and longitudinal analysis, we selected 14 genes for CRISPR knockdown in human white adipose tissue cell lines. In two target genes, knockdown significantly (two-sided t test p < 0.05/14) decreased lipid accumulation: PPARG (fold change [FC] = 0.25, p = 5.52 × 10^-7) and SLTM (FC = 0.51, p = 1.91 × 10^-4); knockdown of COL5A3 (FC = 1.72, p = 0.0028) resulted in significantly increased lipid accumulation. Integrating across population-based genetic and in vitro functional evidence, we highlight therapeutic avenues for altering obesity and body fat distribution by modulating lipid accumulation.

Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B; five individuals harbor a rare missense variant, and one individual has an mRNA splice site change. This cohort is unified by overlapping neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain wherein four of five human disease-associated missense variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we knocked down the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural axons, aligning with symptoms of affected individuals. Ectopic expression of TMEM184B c.550A>G (p.Lys184Glu) and c.484G>A (p.Gly162Arg) variants cause reduced head size and body length, indicating dominant effects, while three other variants show haploinsufficiency. None of the variants are able to rescue the knockdown phenotype. Human induced pluripotent stem cells with monoallelic production of p.Lys184Glu show mRNA disruptions in key metabolic pathways including those controlling mechanistic target of rapamycin activity. Expression of p.Lys184Glu and c.863G>C (p.Gly288Ala) increased apoptosis in cell lines, and p.Lys184Glu increased nuclear localization of transcription factor EB, consistent with a cellular starvation state. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption and result in abnormal neural development.

Micronutrients are essential components of the human diet, but dietary levels above or below their narrow, recommended range are harmful. Deficiencies increase the risk of stunted growth and metabolic, infectious, and respiratory disorders, and have likely been pervasive in human history, as local soils poor in micronutrients are widespread. Deficiencies are also common today, affecting approximately 2 billion people. Limited evidence exists for selenium, zinc, iodine, and iron deficiencies driving local adaptation in a few human populations, but the broader potential role of micronutrients in shaping modern human evolution remains unclear. Here, we investigate signatures of positive selection in 276 genes associated with 13 micronutrients and evaluate whether human adaptation across global populations has been driven by micronutrients. We identify known and previously undescribed instances of rapid local adaptation in micronutrient-associated genes in particular populations, including previously undescribed individual signatures of adaptation across most of the world. Further, we identify signatures of oligogenic-positive selection in multiple populations at different geographic and temporal scales, with some recapitulating known associations of geology and micronutrient deficiencies. We conclude that micronutrient deficiencies have likely shaped worldwide human evolution more directly than previously appreciated and, given the ongoing depletion of soil quality from over-farming and climate change, caution that some populations may be at higher risk of suffering from micronutrient-driven disorders going forward.