Impact of cultural and genetic structure on food choices along the Silk Road.

The complex interplay between genetics, culture, and environment forms an individual's biology, influencing their behavior, choices, and health. However, to what extent information derived from this intertwined network could be quantitatively summarized to provide a glance at an individual's lifestyle is difficult to say. Here, we focused on dietary preferences as cultural proxies and genome-wide data of 543 individuals from six historical Silk Road countries: Georgia, Armenia, Azerbaijan, Uzbekistan, Kazakhstan, and Tajikistan. These lands favored the dispersal of innovations, foods, and DNA halfway across Eurasia, thus representing an ideal subject to explore interactions of cultural factors and genetic ancestry. We used discriminant analysis of principal components to infer cultural clusters, where mixed memberships are allowed. Five different clusters emerged. Of these, clusters 1 and 3, driven by aversion to pork and alcoholic beverages, mirrored genetic admixture patterns with the exception of Azerbaijan, which shares preferences supported by Islamic culture with Eastern countries. Cluster 3 was driven by protein-rich foods, whose preference was significantly related to steppe pastoralist ancestry. Sex and age were secondary clustering factors, with clusters formed by male and young individuals being related to alcohol preference and a reduced liking for vegetables. The soft clustering approach enabled us to model and summarize the individual's dietary information in short and informative vectors, which show meaningful interaction with other nondietary attributes of the studied individuals. Encoding other cultural variables would help summarize an individual's culture quantitatively, thus ultimately supporting its inclusion as a covariate in future association studies.

Runs of homozygosity are associated with staging of periodontitis in isolated populations.

Periodontitis is a common inflammatory disease characterized by a complex etiology, which is the result of a combination of genetic and environmental factors. Genetic variants linked to the periodontitis disease were already investigated, however, little was known regarding the severity of this disease. Recently, long runs of homozygosity (ROH) were associated with several multifactorial diseases. Therefore, in our work, we tried to assess the role of ROH and periodontitis status. We found an association between the excess of homozygosity owing to ROH and staging of periodontitis. More in detail, the total amount of homozygosity owing to ROH is positively associated with an increased severity of periodontitis (P = 0.0001). Regression tree analysis showed the impact of ROH burden in discriminating individuals with mild periodontitis stages I and II and periodontitis stages III and IV (P < 0.001). Furthermore, ROH mapping highlights several regions associated with a severe status of periodontitis (odds ratio > 1). Among them, we found a total of 33 genes. Interestingly, some of these genes were previously associated with granulocyte or platelet measures, both linked to the onset and the progression of periodontal disease. Our results suggest the not only single variants association test could help to risk assessment but even individual genomic features; furthermore, our ROH mapping highlighted the possible role of multiple genes in periodontal development.

Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss.

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.

Relationship between clone metrics and clinical outcome in clonal cytopenia.

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.

50 shades of lockdown: sex workers' hidden world during COVID pandemic.

BACKGROUND: The COVID-19 pandemic had a huge impact on psychological health and socioeconomic structures. The consequences of COVID-19 on the physical, psychological, and social spheres have been extensively studied, except for aspects concerning sexuality and sex workers, in terms of physical, social and economic impact, but also as a possible cause for viral transmission. METHODS: With the intention of counteracting the lack of research, from September 2020 to August 2022, we distributed an anonymous questionnaire to Sex Workers' associations aimed at investigating the impact of the pandemics on sex workers. In the period examined we received and reviewed 147 questionnaires from women, men, and transsexuals. CONCLUSIONS: The prevention of the viral transmission during a pandemic is of utmost importance but should not be exclusively promoted at the expense of other important prevention initiatives. Safeguarding psycho-physical health of the general population, including effective health educational communications emphasizing the importance of sexual activity in mental and physical health should be part of ongoing health objectives. These approaches need to include sex workers of all genders-particularly racialized and marginalized sex workers-in public health planning and messaging alongside structural interventions. Full decriminalization of sex work and access to workplace protections are key to protecting both sex workers' and clients' health. Sex workers of all genders have often been among the first hit by epidemics and the last to be protected-it is long past time to change that.

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Dietary Macronutrient Composition in Relation to Circulating HDL and Non-HDL Cholesterol: A Federated Individual-Level Analysis of Cross-Sectional Data from Adolescents and Adults in 8 European Studies.

BACKGROUND: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined. OBJECTIVE: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data. METHODS: Dietary macronutrient intake was recorded using study-specific dietary assessment tools. Main outcome measures were lipoprotein cholesterol concentrations: HDL cholesterol (mg/dL) and non-HDL cholesterol (mg/dL). A cross-sectional analysis on 5919 participants (54% female) aged 13-80 y was undertaken using the statistical platform DataSHIELD that allows remote/federated nondisclosive analysis of individual-level data. Generalized linear models (GLM) were fitted to assess associations between replacing 5% of energy from carbohydrates with equivalent energy from total fats, SFAs, MUFAs, or PUFAs with circulating HDL cholesterol and non-HDL cholesterol. GLM were adjusted for study source, age, sex, smoking status, alcohol intake and BMI. RESULTS: The replacement of 5% of energy from carbohydrates with total fats or MUFAs was statistically significantly associated with 0.67 mg/dL (95% CI: 0.40, 0.94) or 0.99 mg/dL (95% CI: 0.37, 1.60) higher HDL cholesterol, respectively, but not with non-HDL cholesterol concentrations. The replacement of 5% of energy from carbohydrates with SFAs or PUFAs was not associated with HDL cholesterol, but SFAs were statistically significantly associated with 1.94 mg/dL (95% CI: 0.08, 3.79) higher non-HDL cholesterol, and PUFAs with -3.91 mg/dL (95% CI: -6.98, -0.84) lower non-HDL cholesterol concentrations. A statistically significant interaction by sex for the association of replacing carbohydrates with MUFAs and non-HDL cholesterol was observed, showing a statistically significant inverse association in males and no statistically significant association in females. We observed no statistically significant interaction by age. CONCLUSIONS: The replacement of dietary carbohydrates with fats had favorable effects on lipoprotein cholesterol concentrations in European adolescents and adults when fats were consumed as MUFAs or PUFAs but not as SFAs.

Differences in taste and smell perception between type 2 diabetes mellitus patients and healthy controls.

BACKGROUND AND AIMS: The senses of taste and smell are essential determinants of food choice, which in turn may contribute to the development of chronic diseases, including diabetes. Although past studies have evaluated the relationship between type 2 diabetes mellitus (DM2) and senses disorders, this relationship remains controversial. In this study, we evaluated taste and smell perception in DM2 patients and healthy controls (HC). Moreover, we analyzed the association of chemosensory impairments with anthropometric and clinical outcomes (e.g. Body Mass Index (BMI), Fasting blood glucose (FBG), drugs, cardiovascular diseases (CVD), and hypertension) in DM2 patients. METHODS AND RESULTS: The study included 94 DM2 patients and 244 HC. Taste recognition for 6-n-propylthiouracil (PROP), quinine, citric acid, sucrose, and sodium chloride (NaCl) compounds was assessed using a filter paper method, while smell recognition of 12 odorants was performed using a Sniffin' sticks test. We found that a higher percentage of DM2 patients showed identification impairment in salt taste (22% vs. 5%, p-value<0.0009) and smell recognition (55% vs. 27%, p-value = 0.03) compared to HC. We also observed that 65% of hypertensive DM2 subjects presented smell identification impairment compared to 18% of non-hypertensive patients (p-value = 0.019). Finally, patients with impairments in both taste and smell showed elevated FBG compared to patients without impairment (149.6 vs.124.3 mg/dL, p-value = 0.04). CONCLUSION: The prevalence of taste and smell identification impairments was higher in DM2 patients compared to HC, and a possible relationship with glycemic levels emerged.

Taste perception and expression in stomach of bitter taste receptor tas2r38 in obese and lean subjects.

Differences in taste perception have been related to eating behavior, nutritional status, and diseases. Recently, taste receptors have been identified in several extra-oral tissues, such as the gastrointestinal tract, where they seem to influence processes like digestion, sense of satiety as well as energy balance and intraluminal changes occurring in obesity. Our study aims to analyze differences in taste perception among 42 obese patients (OB) and 41 normal-weight subjects (LEAN). Polymorphisms in the gene codifying for the bitter taste receptor TAS2R38 and its expression on the surface of the gastric mucosa were tested and compared among OB and LEAN. Taste intensity of PROP (6-n-propylthiouracil), quinine, sucrose, citric acid and NaCl were measured on a labeled magnitude scale. DNA from peripheral whole blood was extracted and three polymorphisms in the TAS2R38 gene (rs713598, rs1726866, rs10246939) analyzed. Gastric biopsies were collected during bariatric surgery in OB and during endoscopy in LEAN. RNA was extracted and TAS2R38 gene expression assessed by RT-Real-Time qPCR. Anamnestic and anthropometric data were recorded in all participants during baseline visits. Logistic regression analysis showed that OB perceives sweet (sucrose) and bitter (PROP or 6-n-propylthiouracil) taste more intensely than LEAN (p-value = 0.02 and p-value = 0.005, respectively). While polymorphisms in TAS2R38 gene did not differ among OB and LEAN, we observed a significant increase of TAS2R38 mRNA levels in the stomach of OB compared to LEAN (p = 0.01). Our results provide new evidence of a link between obesity and altered taste perception as well as TAS2R38 expression in the stomach.

A population-based approach for gene prioritization in understanding complex traits.

Gene prioritization is the process of determining which variants and genes identified in genetic analyses are likely to cause a disease or a variation in a phenotype. For many genes, neither in vitro nor in vivo testing is available, thus assessing their pathogenic role could be challenging, leading to false-positive or false-negative results. In this paper, we propose an innovative score of gene prioritization based on the population of interest. We introduce the concept of singleton-cohort variants (SC variant), a variant that has allele count equal to one in the cohort under study. The difference between the normalized count of SC variants in the coding region and the normalized count of SC variants in the non-coding region should give a hint regarding the level of constraints for that gene in a specific population. This scoring system is negative when there are constraints that allow the presence of SC variants only in the non-coding region; on the contrary, it is positive when there are no constraints. A complimentary score is the sum of SC variants normalized count in both coding and non-coding regions, which could be used as a proxy of positive or strong purifying selection in a specific population. Our methodology showed a high level of constraining for genes such as USP34 in all subpopulations tested (1000 G dataset). In contrast, some genes showed a high negative score only in specific populations, e.g., MYT1L in Europeans, UBR5 in East Asians, and FBXO11 in Africans.

Primary Ciliary Dyskinesia: The Impact of Taste Receptor (TAS2R38) Gene Polymorphisms on Disease Outcome and Severity.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to recurrent respiratory infections of upper and lower airways. Chronic rhinosinusitis (CRS) and bronchiectasis are very common in PCD patients. Recently, it has been shown the presence of taste receptors in respiratory tract and the possible involvement of bitter taste receptor TAS2R38 gene in susceptibility to respiratory infections and rhinosinusitis. OBJECTIVE: Aim of this study was to evaluate the frequency of TAS2R38 polymorphisms in PCD patients and their possible correlations with clinical outcomes of the disease. METHODS: Genetic and phenotypic data of 35 PCD patients were collected. Clinical evaluation included neonatal respiratory distress (NRD) at birth, presence of situs inversus, CRS, and bronchiectasis. We also measured the number of respiratory infections per year and the relevant pathogens, Lund-Mackay score, FEV1, and modified Bhalla score. With regard to genetics data, 3 polymorphisms (rs1726866, rs713598, and rs10246939) within TAS2R38 gene were analyzed and the patients were classified as PAV/PAV, PAV/AVI, and AVI/AVI. RESULTS: A significant difference in the distribution of TAS2R38 haplotype between patients with and without NRD emerged (p value = 0.01). A lower percentage of PAV/PAV individuals showed frequent respiratory exacerbations (≥2/year) (p value = 0.04) compared to those with AVI/AVI and AVI/PAV haplotypes. Moreover, no patients homozygous for PAV/PAV haplotype presented chronic colonization by Pseudomonas aeruginosa, thus supporting the possible role of TAS2R38 gene in susceptibility to respiratory infections. CONCLUSIONS: Here, we report, for the first time, a possible association of TAS2R38 polymorphisms with PCD phenotype.

Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss.

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1-/- mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.

Association of LTA gene haploblock with periodontal disease in Italian adults.

BACKGROUND: Periodontitis is a common oral disease caused by host inflammatory response towards bacteria biofilm. The chronic activation of immune response leads to destruction of teeth supporting tissue, bone loss and tooth detachment. Different factors could be involved in the development and severity of the disease; among them the host genetic background should be considered. OBJECTIVES: In our study, we analysed haploblocks in a genomic region within major histocompatibility complex (MHC) locus aimed at disclosing a possible correlation with the risk of periodontal disease in 602 adult subjects from North-East Italy. RESULTS: The CTTAC haploblock (formed by LTA-rs2857709, LTA-rs2844484, LTA- rs2229094, LTA-rs2229092 and LTA-rs1041981 polymorphisms) correlated with protection towards periodontitis condition, after regression analysis including age and smoking status as covariates (P-value = 0.015). CONCLUSION: Our results suggest that a haplotype within LTA gene (encoding for lymphotoxin alpha) is involved in the susceptibility towards chronic periodontitis.

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

Investigation of the link between PROP taste perception and vegetables consumption using FAOSTAT data.

In this work we investigated, in populations located in Central Asia, the relationship between PROP taste perception and vegetables liking and consumption using FAOSTAT dataset. Collected data were analysed using distance matrices, Mantel test and Pearson correlation. Populations showing similar ability in tasting PROP bitterness are more similar as respect to vegetable consumption (r = 0.63, p-value = .05). Moreover, a significant negative correlation was found between the percentage of Non Taster (NT) in different countries and the percentage of vegetable consumption (r = -0.87, p-value = .02), while a significant positive correlation emerged between the percentage of Super Taster (ST) and the percentage of vegetable liking (r = 0.87, p-value = .02). In our work we showed that differences in bitter perception among populations contributes to differences in vegetable liking and vegetable consumption. More in detail, populations with higher percentage of ST consume more vegetables than population where the majority of individuals are NT.

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements.

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.

A genome-wide association study identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population.

BACKGROUND AND OBJECTIVE: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder. METHODS: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect. RESULTS: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P < 5 × 10-8 ), with the best hit on the rs242016 SNP (P = 1.5 × 10-8 ). CONCLUSION: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder.

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Genetic structure in the Sherpa and neighboring Nepalese populations.

BACKGROUND: We set out to describe the fine-scale population structure across the Eastern region of Nepal. To date there is relatively little known about the genetic structure of the Sherpa residing in Nepal and their genetic relationship with the Nepalese. We assembled dense genotype data from a total of 1245 individuals representing Nepal and a variety of different populations resident across the greater Himalayan region including Tibet, China, India, Pakistan, Kazakhstan, Uzbekistan, Tajikistan and Kirghizstan. We performed analysis of principal components, admixture and homozygosity. RESULTS: We identified clear substructure across populations resident in the Himalayan arc, with genetic structure broadly mirroring geographical features of the region. Ethnic subgroups within Nepal show distinct genetic structure, on both admixture and principal component analysis. We detected differential proportions of ancestry from northern Himalayan populations across Nepalese subgroups, with the Nepalese Rai, Magar and Tamang carrying the greatest proportions of Tibetan ancestry. CONCLUSIONS: We show that populations dwelling on the Himalayan plateau have had a clear impact on the Northern Indian gene pool. We illustrate how the Sherpa are a remarkably isolated population, with little gene flow from surrounding Nepalese populations.