Human Genetics最新文献

Dyslipidemia is an important risk factor for cardiovascular diseases and can result from genetic and environmental influences. Most genome-wide association studies (GWAS) have been conducted in European populations, limiting our understanding of polymorphisms involved in lipid levels in admixed populations such as Brazilians. Therefore, this study aimed to identify genetic variants associated with lipid traits and develop polygenic risk scores (PRS) for dyslipidemia prediction in a large cohort of Brazilians. We performed GWAS of lipid phenotypes using 19,016 Brazilian individuals previously genotyped with SNP array and with available biochemical lipid measurements. After quality control and imputation, GWAS analyses were conducted separately for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL cholesterol (non-HDL-C). Trans-ancestry PRS were constructed using PRS-CSx. A set of 161 lead genome-wide significant SNPs were identified across lipid traits, including 62 previously reported in different populations, and many others representing potential novel associations for TC and TG. PRS models showed consistent associations with lipid levels, with increasing prevalence of elevated TC, LDL-C, non-HDL-C, and TG across higher PRS deciles. The area under the curve (AUC) values ranged from 0.62 to 0.66 across traits, with the highest performances for TC, non-HDL-C and TG. This study provides new insights into the genetic architecture of lipid traits in an admixed Brazilian population. Our findings underscore the relevance of conducting GWAS in diverse populations, support the use of PRS for risk stratification and prevention, and point to novel targets for drug development.

The SLC6A14 gene on chromosome X modifies disease presentation in individuals with cystic fibrosis (CF). Population studies have revealed distinct proximal and distal SNP clusters associated with gastrointestinal and lung phenotypes, respectively. Given the co-localization of cis-eQTLs within the corresponding associated chromosomal regions, where less SLC6A14 expression aligns with improved phenotypic outcomes, we sought to understand the SNP contributions to SLC6A14 expression regulation. Using reporter gene assays, we show that the proximal cluster, aligning with pancreas eQTLs, provides variation in promoter activity that is allele-dependent. The more expansive distal cluster, aligning with primary nasal cell eQTLs, was surveyed and found to harbour an enhancer feature that augmented expression in conjunction with the promoter in cells of lung origin. The rs4446858 SNP present within the enhancer aligns with the binding motif of the IRF1 transcription factor, where the alternate C allele was found to respond to direct addition of IRF1 or its increase following IFN-γ stimulation, resulting in increased SLC6A14 expression. Our data support a conclusion that SLC6A14 expression in airway tissue is regulated, in part, by immune-responsive genetic features, likely involving goblet cells. While our findings support previous model system studies indicating beneficial acute effects of SLC6A14 expression, they also highlight a distinction between immune-related responses and cumulative effects of long term disease reflected as lung function in individuals with CF. Our studies emphasize the challenges of elucidating complex genetic loci where there are multiple levels of regulatory influence with competing contributions.

DNA methylation plays a crucial role in the development and progression of cancer and has been utilized for subtyping various tumors. This study focused on classifying epithelial ovarian cancer (EOC) based on DNA methylation and characterizing the subtypes through an integrated analysis of genomic, transcriptomic, and clinical data. We performed genome-wide DNA methylation profiling on 137 EOC tumor tissues using Infinium MethylationEPIC array and four methylation subtypes (MS1-MS4) were identified by non-negative matrix factorization (NMF) approach, showing significant differences in prognosis (P = 2.413 × 10⁻⁹). The MS1 group showed the best prognosis and the most favorable response to paclitaxel in combination with platinum-based chemotherapy. MS2 exhibited a gene expression pattern of relatively high immune cell infiltration and MS3 had a gene expression pattern associated with metabolic related pathway with a moderate prognosis. In contrast, MS4 had the poorest prognosis and was marked by the highest methylation levels among the four subtypes. A four-differential methylation position (DMP) signature was constructed for prognosis prediction and nomogram was also developed for enhancing clinical utility. Together, this study identified a novel molecular subtype for EOC, elucidating the heterogeneity of EOC from an epigenetic perspective and providing a new strategy for personalized treatment options for EOC patients.

Occult hepatitis B virus infection (OBI), characterized by detectable HBV DNA but undetectable HBsAg, poses diagnostic and clinical challenges, with host genetic factors, particularly HLA-mediated immune regulation, remaining poorly understood. Through whole-exome sequencing of 147 participants (74 OBI cases, 73 chronic HBsAg + controls), we identified four HLA single nucleotide polymorphisms (SNPs) associated with low OBI susceptibility and proposed a dual immune mechanism: Class I SNPs impair cytotoxic responses, while Class II SNPs dysregulate humoral immunity. Anti-HBs titers and age modulated genetic risk penetrance, with high anti-HBs increasing OBI susceptibility regardless of genotype, and genetic effects attenuating in individuals > 50 years. Integrating HLA genetic markers with serological and baseline characteristics significantly improved OBI susceptibility prediction (AUC 0.93), highlighting the role of HLA-mediated immunity in OBI pathogenesis and the potential of genetic markers for risk stratification in HBV-exposed individuals. Our findings elucidate HLA-mediated immune mechanisms underlying OBI and demonstrate the value of genetic markers in predicting the likelihood of developing OBI or progressing to chronic HBsAg + status among HBV-exposed individuals.

Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. While previous studies have identified common genetic variants associated with dyslexia, the role of rare variants has only recently begun to emerge from pedigree studies and has yet to be systematically tested in larger cohorts. Here, we present a whole-exome sequencing (WES) study of 53 individuals with dyslexia, followed by an analysis in 38 cases with reading difficulties and 82 controls assessed with reading measures. Of the 22 genes that had high-impact variants filtered through stringent bioinformatic approaches in at least three dyslexia cases, five genes were validated in the follow-up analysis: CACNA1D, CACNA1G, CLDN3, CNGB1, and CP. Notably, a specific variant (7-73769649-G-A; c.C401T; p.P134L) in the CLDN3 gene was identified in six independent cases, showing a four-fold higher frequency compared to population reference datasets. CACNA1D and CACNA1G encode subunits of voltage-gated calcium channels expressed in neurons, and variants in both genes have been implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and epilepsy. Segregation analyses in available family members were consistent with patterns of dominant inheritance with variable expressivity. In total, high-impact variants in the five genes of interest were found in 26% (N = 14) of individuals of the discovery cohort. Overall, our findings support the involvement of rare variants in developmental dyslexia and indicate that larger WES studies may uncover additional associated genes.

In the last decade, substantial research efforts have started worldwide to foster the clinical translation of Polygenic Risk Scores (PRS). Understanding the views of key relevant groups becomes timely to critically inform the socio-ethical debate, impact future health policy, and support the development of guidelines for best practices in healthcare contexts. We performed 26 in-depth semi-structured interviews to investigate the perspectives of European researchers and healthcare providers from different specialties (clinical genetics, oncology, cardiology, psychiatry) on the ethical and social implications of PRS uses in healthcare contexts. Findings were conceptualized in four main themes: 1) appropriate clinical use, highlights that PRS should be considered complementary tools aimed at informing a clinical intervention, with notions of appropriateness differing according to clinical goals and condition-type; 2) clinical utility: what's the evidence? captures participants' orientations towards the capability of PRS to improve health outcomes compared to standard care, as well as the barriers, limitations, or emerging areas of utility; 3) balancing risk and responsibility: navigating ethical questions in patient care, addresses classical issues in clinical genetics, including communication and counselling, potential patient harms, relevance of PRS information to family members, and the use of PRS in pediatric settings; 4) searching for standards: clinical guidelines, gathers perspectives on the potential format and content of future clinical guidelines, relevant parties, and contexts of applicability. In conclusion, the present study outlines a framework to define the range of responsible uses in healthcare contexts; however, societal and public health considerations, including priority-setting in national healthcare systems, need to follow for a comprehensive, and contextual, evaluation of PRS.