HGG Advances最新文献

Homozygous loss-of-function mutations in LNPK, the gene encoding the endoplasmic reticulum-associated protein lunapark, have previously been linked to an autosomal recessive neurodevelopmental syndrome. Here, we describe an individual harboring compound heterozygous predicted splice site mutations with an overall matching phenotype. In cultured fibroblasts, these mutations result in a dearth of transcript and severe loss of protein, thereby establishing their likely pathogenicity. The underlying reduction in gene expression is due to the activation of the nonsense-mediated decay (NMD) pathway as a consequence of exon skipping rather than intron retention, leading to aberrant transcripts. We further demonstrate that cells from the affected individual and her mother exhibit a significant increase in transcript compared with a control cell line when treated with an inhibitor of NMD, suggesting potential genetic compensation. Together, this report describes disease-causing variants in LNPK and reveals their impact on transcription and mRNA stability.

Antidepressants are among the most-prescribed drugs worldwide, and selective serotonin reuptake inhibitors (SSRIs) are among the most prescribed antidepressants, most commonly used for major depression. We sought to increase our understanding of the biological relationships between SSRI use and a range of psychiatric traits by conducting a genome-wide association study (GWAS) in two large datasets, the UK Biobank (UKB) and the US Million Veteran Program (MVP). GWAS was conducted across 22 autosomes and the X chromosome in 777,952 individuals of European ancestry (191,800 SSRI users, 586,152 control individuals) and 112,526 individuals of African ancestry (53,499 SSRI users, 59,027 control individuals). We identified 40 genome-wide significant (GWS) loci, including two on the X chromosome. Using linkage disequilibrium score regression, we detected strong genetic correlations between MVP and the independent UKB cohort for specific SSRIs (fluoxetine rg = 0.82, citalopram rG = 0.89) as well as with headaches (rG = 0.80), major depressive disorder (MDD; rG = 0.77), and spondylosis (rG = 0.84), suggesting stability in trait definition across cohorts. To evaluate differences in genomic variance captured by SSRI use vs. MDD, we performed a comparative rG analysis and found significant differences, most notably for educational attainment (SSRI rG = -0.38, MDD rG = -0.26), cognitive performance (SSRI rG = -0.31, MDD rG = -0.15), and depression (SSRI rG = 0.80, MDD rG = 0.97). In MVP, SSRI use showed greater locus discovery than MDD (28 vs. 17 loci); comparison to a prior GWAS of anxiety symptoms identified only five loci. SSRI use is likely a partial proxy for MDD, while also reflecting distinct features relevant to related disorders such as anxiety.

Eye diseases, including cataracts, glaucoma, diabetes retinopathy, and age-related macular degeneration, are major global health challenges and leading causes of blindness. This study leveraged genome-wide association studies (GWASs) involving over 100,000 individuals, integrating data from the Taiwan Biobank and National Health Insurance Research Database, to identify genetic loci associated with disease onset. Our findings suggest that these conditions are influenced by multifactorial etiologies, as pleiotropic loci including rs10811660, rs4710941, rs2283228, and rs7646518 were identified, linking ocular diseases to metabolic conditions. Notably, a strong genetic correlation was observed between cataract and depression. Mendelian randomization analysis further demonstrated a causal effect of depression on cataract risk, implicating shared biological pathways, particularly oxytocin signaling, in disease pathophysiology. This finding revealed a functional genetic variant near the OXTR gene, highlighting its potential as a causal candidate for genetic diagnosis in precision health. By bridging the gap between genetic discovery and clinical application, this research offers critical insights into shared genetic mechanisms across diverse health domains, paving the way for innovative diagnostic and therapeutic strategies.

SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and symptoms across affected individuals. While haploinsufficiency is the most often described disease mechanism, with the majority of variants consisting of whole- or partial-gene deletions and protein truncating variants with predicted loss of function, approximately one-third of affected individuals carry a SATB2 missense variant with an unknown effect. In this study, we sought to functionally characterize these missense variants to uncover associated pathogenic mechanisms. We combined a set of human cell-based experiments to screen 31 etiological SATB2 missense variants for effects on nuclear localization, global chromatin binding, and transcriptional activity. Our data indicate partial loss-of-function effects for most of the studied missense variants but identify at least eight variants with increased SATB2 function showing a combination (or subset) of features that include stronger co-localization with DNA, decreased nuclear protein mobility suggesting increased overall chromatin binding, and maintained or increased transcriptional activity. These results demonstrate that phenotypes associated with variants in SATB2 may have distinct underlying disease mechanisms, and the data could provide a resource for future studies investigating disease variability and potential therapies for this condition.

We investigated colon cancer genomics and microenvironmental features in the Appalachian Kentucky population, a group with the highest incidence of colon cancer in the United States. We assessed two inter-related risk factors for colon cancer (obesity and abnormal gut bacterial microbiome) and their genetic associations within this population. To evaluate potential unique characteristics of the high-incidence cohort, we compared 99 propensity-matched colon cancer tumors from Appalachian Kentucky patients to 95 non-Appalachian patient tumors to evaluate driver mutations, differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, immune cell populations, and microbiomes in an obesity context. Our comparison identified significant population-specific DEGs and differences in COSMIC signature frequencies, KEGG pathway regulation, pro-carcinogenic immune cell features, microbiome species, and obesity-associated inflammatory and metabolic responses between the cohorts. The findings offer generalizable implications deriving from Appalachian Kentuckians while highlighting the critical importance of population-based studies in colon cancer research.

Chromosomal microarray analysis (CMA) detects pathogenic copy-number variants (pCNVs) and regions of homozygosity (ROHs) in prenatal genetic analysis. This study evaluates the clinical significance of ROH detection in prenatal settings. We reviewed 178 fetuses with ROH detected by CMA among 20,546 fetuses from 2015 to 2023. Clinical and laboratory results, including ultrasound anomalies, cell-free DNA (cfDNA) screening, karyotyping, exome sequencing (ES), and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), were analyzed. These 178 fetuses with ROH accounted for 0.87% of prenatal cases. Among them, 24.2% had positive cfDNA screening results, and 52.8% underwent follow-up ES, trio CMA, and MS-MLPA. Follow-up studies detected pathogenic homozygous variants within ROH in two fetuses and uniparental disomy (UPD)-related diseases in five fetuses. Our results and findings from the other five large prenatal case series from literature indicated that ROH detection in prenatal CMA has a baseline positive predictive value of 2.7% for autosomal-recessive disorders, 9.6% for UPD-related diseases, and 0.04% overall additive diagnostic yield. These findings support the use of ES and MS-MLPA for follow-up testing and provide guidance for genetic counseling in fetuses with ROH.

Depression is a frequent focus of interest in genetic testing. Despite the growing availability of polygenic risk scores (PRSs) for depression, little is known about the psychological impact of receiving them in real-world settings. To quantify the impact of receiving an at-risk depression PRS result on depression and anxiety symptoms, we conducted a longitudinal, prospective cohort study of 23andMe research participants. Eligible participants were US residents 18 years old and older who completed two surveys between October 19, 2022 and October 9, 2023 assessing depression and anxiety symptoms and who had an at-risk PRS for depression (odds ratio ≥1.5). We compared 361 individuals who viewed their result with 556 who did not. Primary outcomes were changes in depression (Patient Health Questionnaire-8) and anxiety (Depression Anxiety Stress Scale-21) symptom scores relative to baseline. We fitted linear regressions to model each outcome, adjusting for age, sex, ancestry, income, prior depression and/or anxiety, and baseline scores. Using an equivalence testing framework, the smallest effect size of interest was defined as Cohen's d = ±0.5. Score changes from baseline to follow-up were statistically equivalent for individuals who viewed results and those who did not (adjusted between-group differences in score changes: depression, -0.17 points [90% confidence interval {CI} -0.59 to 0.24]; anxiety, -0.092 points [90% CI -0.35 to 0.17]; all p < 0.001). Results were consistent in substrata with or without prior depression or anxiety. We conclude that among genetically at-risk individuals, exposure to a depression PRS result was well tolerated in a real-world setting.

Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAAs), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.Phe264Leu; c.1042G>A p.Glu348Lys) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1 disease neurons, suggesting a downstream impact on electron transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.

Pleiotropy, the phenomenon where a genetic region confers risk to multiple traits, is widely observed, even among seemingly unrelated traits. Knowledge of pleiotropy can improve understanding of biological mechanisms of diseases/traits, and can potentially guide identification of molecular targets or help predict side effects in drug development. However, statistical approaches for identifying pleiotropy genome-wide are limited, particularly for two correlated traits or case-control traits with unknown sample overlap or for disease traits from family studies. We proposed PLACO+, an improved version of our pleiotropic analysis under composite null hypothesis method based on GWAS summary statistics from two traits. PLACO+ uses an inflated variance model to allow for fractions of variants to be associated with none or only one trait under the null. It is genome-wide scalable, where analytical p value is computed as a weighted sum of extreme tail probabilities of bivariate normal product distribution. Simulations for both population-based and family-based designs demonstrate well-calibrated type I errors at stringent levels and substantially improved power of PLACO+ over conventional approaches. We illustrate PLACO+ on inflammatory bowel disease subtypes with shared controls and on correlated lipid traits with unknown sample overlap. In particular, PLACO+ revealed pleiotropic regions between triglyceride and high-density lipoprotein levels that conventional approaches missed and all of which were replicated in a larger GWAS of these lipid traits. This further demonstrates the utility of PLACO+ in discovering genetic associations of traits with modest sample sizes by leveraging information from another correlated trait.

The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDGs). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense variant in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to the disease pathogenesis of ZIP8 A391T-associated Crohn disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying ZIP8 variants. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.