Association Of Variants Research Articles

Mapping associations of polygenic scores with autistic and ADHD traits in a single city region.

The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants? We mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N = 4,255-6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD. Our results suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences. These findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autistic and ADHD traits.

Association of a NLRP3 rs10754558 Polymorphism with the Development of Chronic Helicobacter pylori Infection in South Indian Tamils

The increased prevalence of Helicobacter pylori infection and inadequate genetic research on the same, demands a genetic study among Tamil population of South India to unravel the association of NLRP3 (NLR family pyrin domain containing 3) variants with persistent H. pylori infection. This research was aimed to study the correlation between persistent H. pylori infection and influence of such genetic variants in the development of disease progression. In this study, 200 healthy volunteers and 120 H. pylori-positive cases were screened for two NLRP3 variants, rs74163773 and rs10754558, using allele-specific PCR and TaqManTM SNP genotyping assay, respectively. Based on our genotype and allelic distribution, rs74163773 variant did not associate with the risk of developing the persistent infection. However, a significant association of heterozygous CG variant of rs10754558 with patient showing clinical symptoms of gastritis, PUD and persistent infection in the over-dominant, co-dominant and recessive models was found. Our findings suggest that persistent H. pylori infection susceptibility was influenced by genetic variant rs10754558 and its heterozygous CG variant can serve as an independent risk factor in the manifestation of chronic gastritis and PUD in the South Indian Tamils.

Novel PTPRQ variants associated with hearing loss in a Chinese family PTPRQ variants in Chinese hearing loss.

Hearing loss is one of the most prevalent congenital sensory disorders. Over 50% of congenital hearing loss cases are attributed to genetic factors. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q, which plays an important role in maintaining the structure and function of the stereocilia of hair cells. Variants in the PTPRQ gene have been implicated in hereditary sensorineural hearing loss. Utilizing next-generation sequencing technology, we identified novel compound heterozygous variants (c.977G>A:p.W326X and c.6742C>T:p.Q2248X) in the PTPRQ gene within a Chinese national lineage, marking the first association of these variants with hereditary sensorineural hearing loss. Our findings further emphasize the critical role of PTPRQ in auditory function and contribute to a more comprehensive understanding of PTPRQ-associated hearing loss mechanisms, aiding in clinical management and genetic counseling.

Association of rare and common genetic variants in MOCOS with inadequate response to allopurinol.

The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5-6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20μmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response. There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.

Pilot association of common NOS3 variants with Preeclampsia risk in Russian pregnant women from Rostov region

Preeclampsia (PE) is a severe medical condition affecting pregnant women, often developing after 20 weeks, and is the most common serious disorder during pregnancy, contributing to 2%-8% of pregnancy-related complications worldwide. The goal of this study is to investigate the association of two genetic variants in NOS3 (-786T&gt;C; rs2070744) and (894G&gt;T; rs1799983) with the risk of developing PE in Russian pregnant women from Rostov region. The case–control study involved 106 pregnant women (46 pregnant women with PE and 60 healthy controls). Genotyping of the selected NOS3 genetic variants (-786T&gt;C) and (894G&gt;T) was done using allele specific RT-PCR. Multifactor dimensionality reduction (MDR) was used to assess the relationship between the SNP-SNP interaction and risk of developing PE. In addition, we analyzed the linkage disequilibrium (LD), and haplotypes association for the selected SNPs in the studied population. According to our results, both NOS3 polymorphisms were statistically significant (P=0.004 and P=0.045, respectively). The NOS3 -786(TT) genotype (OR=0.25 95% CI [0.11- 0.58]) and the NOS3 894(GG) genotype (OR=0.38 95% CI [0.17- 0.84]) were associated with low risk of developing PE. While -786(TC) genotype (OR=4.17 95% CI [1.76-9.85]), 894(GT) (OR=2.48 95% CI [1.10-5.63]) and dominant model of NOS3 (-786T&gt;C) TC+CC (OR=3.97 95% CI [1.72-9.14]) as well as the dominant model GT+TT of NOS3 (894G&gt;T) (OR=2.64 95% CI [1.20-5.82]) were associated with increased risk of PE. In addition, the polymorphism -786(C) allele (OR=2.21 95% CI [1.23-3.98]) and polymorphism 894(T) allele (OR=2.14 95% CI [1.15-4.01]) were both associated with an increased risk of PE. According to the MDR results, the SNP-SNP interaction was statistically significant (P=0.0003). Moreover, two haplotypes of NOS3 gene variants -786C*894G (OR=3.01 95% CI [1.15- 7.86]; P=0.027) and -786C*894T (OR=3.03 95% CI [1.27-7.23]; P=0.014) were shown to be statistically related with an elevated risk of PE. Преэклампсия (ПЭ) − тяжелое заболевание, поражающее беременных женщин, часто развивается после 20 недель гестации, и является наиболее распространенным серьезным расстройством, составляя 2-8% осложнений, связанных с беременностью, во всем мире. Цель исследования: изучить ассоциацию двух вариантов в гене NOS3 (-786T&gt;C; rs2070744) и (894G&gt;T; rs1799983) с риском развития ПЭ у российских беременных женщин из Ростовской области. В исследование типа «случай-контроль» были включены 106 беременных женщин (46 с ПЭ и 60 здоровых, составивших контрольную группу). Генотипирование выбранных генетических вариантов NOS3 (-786T&gt;C) и (894G&gt;T) проводилось методом аллель-специфической RT-PCR. Для оценки взаимодействия SNP-SNP с риском развития ПЭ использовали многофакторное снижение размерности (MDR). Кроме того, мы проанализировали неравновесие по сцеплению (LD) и ассоциацию гаплотипов выбранных SNP в исследуемой популяции. Согласно нашим результатам, оба полиморфизма NOS3 были статистически значимы (р=0,004 и р=0,045, соответственно). Генотип NOS3 -786(TT) (OR=0,25 95% CI [0,11- 0,58]) и генотип NOS3 894(GG) (OR=0,38 95% CI [0,17- 0,84]) были ассоциированы с низким риском развития ПЭ. Генотипы -786(TC) (OR=4,17 95% CI [1,76-9,85]), 894(GT) (OR=2,48 95% CI [1,10-5,63]) и доминантная модель NOS3 (-786T&gt;C) TC+CC (OR=3. 97 95% CI [1,72-9,14]), а также доминантная модель GT+TT NOS3 (894G&gt;T) (OR=2,64 95% CI [1,20- 5,82]) были связаны с повышенным риском развития ПЭ. Кроме того, аллели -786(C) (OR=2,21 95% CI [1,23-3,98]) и 894(T) (OR=2,14 95% CI [1,15-4,01]) были ассоциированы с повышенным риском ПЭ. Взаимодействие SNP-SNP было статистически значимым (р=0,0003). Кроме того, было показано, что два гаплотипа вариантов гена NOS3 -786C*894G (OR=3,01 95% CI [1,15-7,86]; р=0,027) и -786C*894T (OR=3,03 95% CI [1,27-7,23]; р=0,014) статистически значимо ассоциированы с повышенным риском ПЭ.

Gene Variants in Components of the microRNA Processing Pathway in Chronic Myeloid Leukemia.

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk.

Genetic associations and parent-of-origin effects of PVRL1 in non-syndromic cleft lip with or without cleft palate across multiple ethnic populations.

This study investigated the associations of PVRL1 gene variants with non-syndromic cleft lip with or without cleft palate (NSCL/P) by evaluating transmission distortion and parent-of-origin (POO) effects in multiple ethnic populations. We conducted allelic and genotypic transmission disequilibrium tests (TDT) on 10 single-nucleotide variants (SNVs) in PVRL1 using data from 142 Korean families with an affected child. POO effects were analyzed using the POO likelihood ratio test, comparing transmission rates of maternally and paternally inherited alleles. To assess generalizability and ethnic heterogeneity, we compared results from Korean families with data from the Center for Craniofacial and Dental Genetics, which included 2,226 individuals from 497 European and 245 Asian trios. TDT analysis identified significant over-transmission of the rs7940667 (G361V) C allele in Korean families (p=0.007), a finding replicated in both Asian (p=6.5×10-7) and European families (p=1.6×10-10). Eight SNVs showed strong TDT evidence in larger Asian and European datasets after multiple comparison corrections (p<0.0073). Of these, 4 SNVs (rs7940667, rs7103685, rs7129848, and rs4409845) showed particularly robust association (p<5×10-8). POO analysis revealed significant maternal over-transmission of the rs10790330-A allele in Korean families (p=0.044). This finding was replicated in European families (p=9.0×10-4). Additionally, 3 other SNVs, rs7129848 (p=0.001) and the linked SNVs rs3935406 and rs10892434 (p=0.025), exhibited maternal over-transmission in the validation datasets. Our findings provide robust evidence supporting the associations of PVRL1 variants with NSCL/P susceptibility. Further research is necessary to explore the potential clinical applications of these findings.

Polymorphisms in the Growth Hormone Gene and Their Association with Pre-pullet Body Weight in Kuttanad Ducks of Kerala, India

Background: Kuttanad ducks are dual purpose native ducks found in Kerala state of India. Identification of single nucleotide variations in candidate genes like growth hormone gene and exploring their association with body weight at grower and pre-pullet stages is essential for the marker assisted selection of breeder ducks for genetic improvement. Methods: Genomic DNA was extracted from blood samples collected from 101 Kuttanad ducks. PCR-amplification of two duck growth hormone gene (dGH) loci viz, exon 3 and partial intron 3 (227 bp), exon 5 and partial intron 4 (366 bp) were undertaken using custom-synthesised primers. The 366 bp region was genotyped using Single Strand Conformation Polymorphism. The 227 bp region was genotyped using DNA pooling assay to yield a 139 bp product for subsequent High-Resolution Melting analysis. The association of dGH genotypic variants for these loci with fortnightly body weight at pre-pullet stages up to 16 weeks of age was analysed. Result: In the 366 bp fragment, GG and GA genotypes were revealed with one novel SNP (g 74G greater than A). The GG homozygotes had significantly higher body weight at all stages from two to 14 weeks of age (p≤0.01). A novel SNP (g 71A greater than G) was revealed at the 139 bp locus within the 227 bp region with three genotypes viz., AA, AG and GG. The GG homozygotes had significantly higher body weight at six, 14 and 16 weeks of age (p≤0.05). The study revealed that dGH polymorphic loci have jointly contributed to the variation in growth and hence can be used as markers for the primary selection of growers at sixth week of age followed by their secondary selection at 14-16 weeks of age during the multi-stage selection programmes for breeder ducks.

Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Association of Very Rare NOTCH2 Variants with Clinical Features of Alagille Syndrome.

Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 (JAG1) and Notch Receptor 2 (NOTCH2). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs. Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed. We identified eleven rare NOTCH2 variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain. Our results increased the knowledge about NOTCH2 variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS.

Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson’s disease pathogenesis

Activation of the NLRP3 inflammasome has been implicated in Parkinson’s disease (PD) based on in vitro and in vivo studies. Clinical trials targeting the NLRP3 inflammasome in PD are ongoing. However, the evidence supporting NLRP3’s involvement in PD from human genetics data is limited. We analyzed common and rare variants in NLRP3 inflammasome-related genes in PD cohorts, performed pathway-specific polygenic risk score (PRS) analyses, and studied causal associations using Mendelian randomization (MR) with the NLRP3 components and the cytokines IL-1β and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway PRS with PD. MR suggests that altering the expression of the NLRP3 inflammasome, IL-1β, or IL-18, does not affect PD risk or progression. Therefore, our results do not support a role for the NLRP3 inflammasome in PD pathogenesis or as a target for drug development.

Hemoglobin polymorphism and its association with morphometric and egg production traits in Ethiopian indigenous and Sasso chicken breeds.

The present study investigated the biochemical polymorphism of hemoglobin (Hb) and its relationship with performance traits of Ethiopian indigenous and Sasso chicken breeds. A total of 284 chickens reared in three agro-ecologies were examined for genetic diversity and associations with productive traits at Hb locus using agarose gel electrophoresis. The results showed that the HbA allele was dominant in both breeds, and a higher proportion of male chickens were HbAA genotypes, while females were predominantly HbBB types. In the highland agro-ecology, chickens with the HbAA genotype were the most dominant, whereas in mid- and low-land agro-ecologies, chickens with HbBB and HbAB genotypes were found to be more frequent. A moderate level of expected heterozygosity was obtained with 0.47 and 0.445 for indigenous and Sasso chickens, respectively, with an average effective number of alleles per locus of 1.89 and 1.80. Moreover, chickens with HbAA genotypes showed significantly (p ≤ 0.05) higher body weight and linear body measurements than those of HbAB and HbBB genotypes. However, for appendage body structures (comb and wattle dimensions), chickens with the HbAB and HbBB genotypes had higher mean values. Additionally, clutch size (14.2 ± 0.4), clutch length (21.8 ± 0.7), and eight-month egg production (84.1 ± 1.2) were significantly (p ≤ 0.05) higher for hens with HbBB genotypes, followed by those with HbAB-types. Therefore, the considerable hemoglobin variability and significant associations of Hb variants with the performance traits can be sought as guiding information for further genetic improvement interventions in the chicken breeds under investigation. Further microsatellite marker-based genotyping is recommended to validate the higher morphometric values for HbAA genotypes and the better egg production for HbBB and HbAB genotypes.

Assessment of ability of AlphaMissense to identify variants affecting susceptibility to common disease.

An important issue in the analysis of rare variant association studies is the ability to annotate nonsynonymous variants in terms of their likely importance as affecting protein function. To address this, AlphaMissense was recently released and was shown to have good performance using benchmarks based on variants causing severe disease and on functional assays. Here, we assess the performance of AlphaMissense across 18 genes which had previously demonstrated association between rare coding variants and hyperlipidaemia, hypertension or type 2 diabetes. The strength of evidence in favour of association, expressed as the signed log p value (SLP), was compared between AlphaMissense and 43 other annotation methods. The results demonstrated marked variability between genes regarding the extent to which nonsynonymous variants contributed to evidence for association and also between the performance of different methods of annotating the nonsynonymous variants. Although AlphaMissense produced the highest SLP on average across genes, it produced the maximum SLP for only 4 genes. For some genes, other methods produced a considerably higher SLP and there were examples of genes where AlphaMissense produced no evidence for association while another method performed well. The marked inconsistency across genes means that it is difficult to decide on an optimal method of analysis of sequence data. The fact that different methods perform well for different genes suggests that if one wished to use sequence data for individual risk prediction then gene-specific annotation methods should be used.

Abstract Mo078: Identifying Genetic Determinants of Phytosterol Levels: A Genome-Wide Association and Meta-Analysis Study Unveils a New Locus Influencing Campesterol Serum Concentrations

Background: Sitosterolemia, a rare inherited disorder, stems from mutations in the ABCG5/ABCG8 genes, which play a critical role in plant sterol transport. These genetic anomalies result in reduced phytosterol excretion, causing an accumulation in the body that can lead to serious health issues, such as premature coronary artery disease. Hypothesis: The study aimed to uncover the genetic determinants influencing plant sterol levels within the Middle East/North Africa (MENA) population, focusing on individuals from Qatar. It hypothesized that unique genetic variations might influence these levels, contributing to the development of sitosterolemia. Aims: To conduct the first genome-wide association study (GWAS) in the MENA region to identify genetic variants affecting plant sterol levels in the Qatari population, and to compare these findings with those from populations of European ancestry. Methods: The study utilized the Metabolon platform for analyzing serum levels of β-sitosterol and campesterol, combined with genome sequence data from the Qatar Genome Program. A trans-ancestry meta-analysis compared our findings with those from a large European cohort, while conditional analysis helped identify specific single nucleotide polymorphisms (SNPs) associated with these sterols. Results: The research identified two independent SNPs related to β-sitosterol ((rs145164937 and rs4299376) and two to campesterol (rs7598542 and rs75901165) in the Qatari population, alongside previously reported variants ( P &lt;5.0 ×10 -8 ) .Notably, one variant (rs75901165) was located in the Intraflagellar Transport 43 (IFT43) gene, diverging from the common ABCG5/8 locus. The study also supported the association of variants in the SCARB1 and ABO genes with sitosterolemia and assessed a polygenic risk score's efficacy based on European GWAS data in the Qatari cohort. Conclusion(s): The findings underscore the significance of conducting population-specific genetic research to understand better and manage conditions like sitosterolemia. This research highlights the importance of personalized treatment approaches for hyperlipidemia and the value of establishing comprehensive multi-omics databases tailored to specific populations.

Bayesian Rare Variant Analysis Identifies Novel Schizophrenia Putative Risk Genes.

The genetics of schizophrenia is so complex that it involves both common variants and rare variants. Rare variant association studies of schizophrenia are challenging because statistical methods for rare variant analysis are under-powered due to the rarity of rare variants. The recent Schizophrenia Exome meta-analysis (SCHEMA) consortium, the largest consortium in this field to date, has successfully identified 10 schizophrenia risk genes from ultra-rare variants by burden test, while more risk genes remain to be discovered by more powerful rare variant association test methods. In this study, we use a recently developed Bayesian rare variant association method that is powerful for detecting sparse rare risk variants that implicates 88 new candidate risk genes associated with schizophrenia from the SCHEMA case-control sample. These newly identified genes are significantly enriched in autism risk genes and GO enrichment analysis indicates that new candidate risk genes are involved in mechanosensory behavior, regulation of cell size, neuron projection morphogenesis, and plasma-membrane-bounded cell projection morphogenesis, that may provide new insights on the etiology of schizophrenia.

Genetic associations with human longevity are enriched for oncogenic genes.

Human lifespan is shaped by both genetic and environmental exposures and their interaction. To enable precision health, it is essential to understand how genetic variants contribute to earlier death or prolonged survival. In this study, we tested the association of common genetic variants and the burden of rare non-synonymous variants in a survival analysis, using age-at-death (N = 35,551, median [min, max] = 72.4 [40.9, 85.2]), and last-known-age (N = 358,282, median [min, max] = 71.9 [52.6, 88.7]), in European ancestry participants of the UK Biobank. The associations we identified seemed predominantly driven by cancer, likely due to the age range of the cohort. Common variant analysis highlighted three longevity-associated loci: APOE, ZSCAN23, and MUC5B. We identified six genes whose burden of loss-of-function variants is significantly associated with reduced lifespan: TET2, ATM, BRCA2, CKMT1B, BRCA1 and ASXL1. Additionally, in eight genes, the burden of pathogenic missense variants was associated with reduced lifespan: DNMT3A, SF3B1, CHL1, TET2, PTEN, SOX21, TP53 and SRSF2. Most of these genes have previously been linked to oncogenic-related pathways and some are linked to and are known to harbor somatic variants that predispose to clonal hematopoiesis. A direction-agnostic (SKAT-O) approach additionally identified significant associations with C1orf52, TERT, IDH2, and RLIM, highlighting a link between telomerase function and longevity as well as identifying additional oncogenic genes. Our results emphasize the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.

A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer.

Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

Association of CTLA-4 (AT)n Variants in Basal Cell Carcinoma and Squamous Cell Carcinoma Patients from Western Mexico.

The incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is constantly increasing, becoming a significant health problem. CTLA-4 is a critical immune checkpoint, and it has been suggested that a variant of variable-number tandem repeat in the 3'-UTR of its gene, known as (AT)n, may be associated with a higher susceptibility to some cancers; however, little is known about genetic variants of the CTLA-4 gene in NMSC. To establish the association of this genetic variant in the CTLA-4 gene with the susceptibility of NMSC carcinogenesis in the Western Mexican population, samples from 150 BCC patients, 150 SCC patients, and 150 healthy individuals as the reference group (RG) were analyzed by endpoint PCR, followed by electrophoresis to genotype the samples. We found that the short-repeat 104/104 bp genotype may be a risk factor for BBC carcinogens (OR = 2.92, p = 0.03), whereas the long-repeat 106/106 bp genotype may be a protective factor for both BCC (OR = 0.13, p = 0.01) and SCC (OR = 0.32, p = 0.01) susceptibility. Our results show that in the Western Mexican population, long-repeat (AT)n variants in the CTLA-4 gene are associated with a protective factor in BCC and SCC. In contrast, short repeats are associated with a risk factor.

Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.

Testing Reported Associations of Gene Variants with Non-Syndromic Orofacial Clefts in the Polish Population.

Orofacial clefts (OFCs) are the second most common birth defect worldwide. The etiology of OFCs involves complex interactions between genetics and environment. Advances in genomic technologies have identified gene variants associated with OFCs. This study aimed to investigate whether selected SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes influence the occurrence of non-syndromic OFCs in the Polish population. The study included 209 individuals with non-syndromic OFCs and 418 healthy controls. Saliva and umbilical cord blood samples were collected for DNA extraction. Four SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes were genotyped using real-time PCR-based TaqMan assays. Statistical analysis was performed using logistic regression to assess the association between SNPs and OFCs. A significant association was found between the rs7078 CC polymorphism and OFCs (OR = 3.22, CI 1.68-6.17, p < 0.001). No significant associations were identified for the rs1081131, rs13041247, and rs3769817 polymorphisms. The research indicates that the rs7078 polymorphism significantly influences the occurrence of orofacial cleft palate in the Polish population, whereas the rs3769817, rs1801131, and rs13041247 SNPs do not show such a correlation.