Monogenic forms of DSD: An update

DSD encompasses a wide range of pathologies that impact gonad formation, development and function in both 46,XX and 46,XY individuals. The majority of these conditions are considered to be monogenic, although the expression of the phenotype may be influenced by genetic modifiers. Although considered monogenic, establishing the genetic etiology in DSD has been difficult compared to other congenital disorders for a number of reasons including the absence of family cases for classical genetic association studies and the lack of evolutionary conservation of key genetic factors involved in gonad formation. In recent years, the widespread use of genomic sequencing technologies has resulted in multiple genes being identified and proposed as novel monogenic causes of 46,XX and/or 46,XY DSD. In this review, we will focus on the main genomic findings of recent years, which consists of new candidate genes or loci for DSD as well as new reproductive phenotypes associated with genes that are well established to cause DSD. For each gene or loci, we summarise the data that is currently available in favor of or against a role for these genes in DSD or the contribution of genomic variants within well-established genes to a new reproductive phenotype. Based on this analysis we propose a series of recommendations that should aid the interpretation of genomic data and ultimately help to improve the accuracy and yield genetic diagnosis of DSD.

dbGSRV: a manually curated database of genetic susceptibility to respiratory virus

Human genetics has been proposed to play an essential role in inter-individual differences in respiratory virus infection occurrence and outcomes. To systematically understand human genetic contributions to respiratory virus infection, we developed the database dbGSRV, a manually curated database that integrated the host genetic susceptibility and severity studies of respiratory viruses scattered over literatures in PubMed. At present, dbGSRV contains 1932 records of genetic association studies relating 1010 unique variants and seven respiratory viruses, manually curated from 168 published articles. Users can access the records by quick searching, batch searching, advanced searching and browsing. Reference information, infection status, population information, mutation information and disease relationship are provided for each record, as well as hyper links to public databases in convenient of users accessing more information. In addition, a visual overview of the topological network relationship between respiratory viruses and associated genes is provided. Therefore, dbGSRV offers a promising avenue to facilitate researchers to dissect human factors in respiratory virus infection, define novel drug targets, conduct risk stratification of population and develop personalized medicine approaches. Database URL: http://www.ehbio.com/dbGSRV/front/

Single nucleotide polymorphism in Interleukin 1 alpha gene might be involved in the Oral Herpes recurrent episodes in Brazilian Para-Athletes

The main goal of this study was to investigate if there is an association between Oral Herpes (OH) recurrent episodes and Single Nucleotide Polymorphisms (SNPs) in IL1A, IL10, and IL1RN genes in a group of Brazilian Para-athletes. This transversal study was prepared according to the STrengthening the REporting of Genetic Association Studies (STREGA) guidelines. Oral examination and DNA collection for genotyping were performed in a non-probabilistic convenience sampling composed of Brazilian para-athletes who participated in a Brazilian selective competition. Data referring to the general characterization of sample were collected through a self-reported questionnaire. Candidate genes were chosen with the UCSC Genome Browser and SNPs in IL1A gene (rs17561, rs1304037), IL10 gene (rs1800871), and IL1RN gene (rs9005) were selected and investigated in allelic, genotypic, dominant, and recessive models. Hardy-Weinberg equilibrium was evaluated in each SNP. The sample was composed of 273 para-athletes (63 (23.4%) practice swimming, 61 (22.3%) powerlifting and 145 (63.7%) athletics). OH recurrent episodes was related by 47 (17.2%) para-athletes and the presence of T allele in the rs1304037 increased chance of OH. These findings suggest that rs1304037 in IL1A gene is associated with OH recurrent episodes in para-athletes.

COVID-19 and Indian population: a comparative genetic analysis

Background Major risk factors of COVID-19 include older age, male gender, and comorbidities. In addition, host genetic makeup is also known to play a major role in COVID-19 susceptibility and severity. To assess the genetic predisposition of the Indian population to COVID-19, a comparative analysis of the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes was done between the Indian population and other major populations (European, African, East Asian, South Asian, and American). Materials and methods Polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and mortality were mined from genetic association studies, comparative genetic studies, expression quantitative trait loci studies among others. Genotype data of these polymorphisms were either sourced from the GenomegaDB database of Mapmygenome India Ltd. (sample size = 3054; Indian origin) or were imputed. Polymorphisms with minor allele frequency >= 0.05 and that are in Hardy-Weinberg equilibrium in the Indian population were considered for allele frequency comparison between the Indian population and 1000 Genome population groups. Results Allele frequencies of 421 polymorphisms were found to be significantly different in the Indian population compared to European, African, East Asian, South Asian, and American populations. 128 polymorphisms were shortlisted based on linkage disequilibrium and were analyzed in detail. Apart from well-studied genes, like ACE2, TMPRSS2, ADAM17, and FURIN, variants from AHSG, IFITM3, PTPN2, CD209, CCL5, HEATR9, SELENBP9, AGO1, HLA-G, MX1, ICAM3, MUC5B, CRP, C1GALT1, and other genes were also found to be significantly different in Indian population. These variants might be implicated in COVID-19 susceptibility and progression. Conclusion Our comparative study unraveled multiple genetic variants whose allele frequencies were significantly different in the Indian population and might have a potential role in COVID-19 susceptibility, its severity, and fatal outcomes. This study can be very useful for selecting candidate genes/variants for future COVID-19 related genetic association studies.

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

Non-alcoholic fatty liver disease (NAFLD) is a continuous progression of pathophysiologic stages that is challenging to diagnose due to its inherent heterogeneity and poor standardization across a wide variety of diagnostic measures. NAFLD is heritable, and several loci have been robustly associated with various stages of disease. In the past few years, larger genetic association studies using new methodology have identified novel genes associated with NAFLD, some of which have shown therapeutic promise. This mini-review provides an overview of the heterogeneity in NAFLD phenotypes and diagnostic methods, discusses genetic associations in relation to the specific stages for which they were identified, and offers a perspective on the design of future genetic mapping studies to accelerate therapeutic target identification.

A systematic review and meta-analysis of host genetic factors associated with influenza severity

Background The severity of influenza disease can range from mild symptoms to severe respiratory failure and can partly be explained by host genetic factors that predisposes the host to severe influenza. Here, we aimed to summarize the current state of evidence that host genetic variants play a role in the susceptibility to severe influenza infection by conducting a systematic review and performing a meta-analysis for all markers with at least three or more data entries. Results A total of 34 primary human genetic association studies were identified that investigated a total of 20 different genes. The only significant pooled ORs were retrieved for the rs12252 polymorphism: an overall OR of 1.52 (95% CI [1.06–2.17]) for the rs12252-C allele compared to the rs12252-T allele. A stratified analysis by ethnicity revealed opposite effects in different populations. Conclusion With exception for the rs12252 polymorphism, we could not identify specific genetic polymorphisms to be associated with severe influenza infection in a pooled meta-analysis. This advocates for the use of large, hypothesis-free, genome-wide association studies that account for the polygenic nature and the interactions with other host, pathogen and environmental factors.

Best practices of multi-ancestry, meta-analytic transcriptome-wide association studies: lessons from the Global Biobank Meta-analysis Initiative

The Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in implementing statistical genetics methods. Transcriptome-wide association studies (TWAS) are a popular tool to boost detection power for and provide biological context to genetic associations by integrating single nucleotide polymorphism to trait (SNP-trait) associations from genome-wide association studies (GWAS) with SNP-based predictive models of gene expression. TWAS presents unique challenges beyond GWAS, especially in a multi-biobank and meta-analytic setting like the GBMI. In this work, we present the GBMI TWAS pipeline, outlining practical considerations for ancestry and tissue specificity and meta-analytic strategies, as well as open challenges at every step of the framework. Our work provides a strong foundation for adding tissue-specific gene expression context to biobank-linked genetic association studies, allowing for ancestry-aware discovery to accelerate genomic medicine.

The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad

Background The genetic association studies of type 2 diabetes mellitus (T2DM) hitherto undertaken among the Indian populations are grossly inadequate representation of the ethnic and geographic heterogeneity of the country. In view of this and due to the inconsistent nature of the results of genetic association studies, it would be prudent to undertake large scale studies in different regions of India considering wide spectrum of variants from the relevant pathophysiological pathways. Given the reproductive dysfunctions associated with T2DM, it would be also interesting to explore if some of the reproductive pathway genes are associated with T2DM. The present study is an attempt to examine these aspects in the southern Indian population of Hyderabad. Methods A prioritized panel of 92 SNPs from a large number of metabolic and reproductive pathway genes was genotyped on 500 cases and 500 controls, matched for ethnicity, age and BMI, using AGENA MassARRAYiPLEX™ platform. Results The allelic association results suggested 14 SNPs to be significantly associated with T2DM at P ≤ 0.05 and seven of those—rs2241766-G (ADIPOQ), rs6494730-T (FEM1B), rs1799817-A and rs2059806-T (INSR), rs11745088-C (FST), rs9939609-A and rs9940128-A (FTO)—remained highly significant even after correction for multiple testing. A great majority of the significant SNPs were risk in nature. The ROC analysis of the risk scores of the significant SNPs yielded an area under curve of 0.787, suggesting substantial power of our study to confer these genetic variants as predictors of risk for T2DM. Conclusions The associated SNPs of this study are known to be specifically related to insulin signaling, fatty acid metabolism and reproductive pathway genes and possibly suggesting the role of overlapping phenotypic features of insulin resistance, obesity and reproductive dysfunctions inherent in the development of diabetes. Large scale studies involving gender specific approach may be required in order to identify the precise nature of population and gender specific risk profiles for different populations, which might be somewhat distinct.

Assortative mating and within-spouse pair comparisons

Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias.

Effect of PTPN22, FAS/FASL, IL2RA and CTLA4 genetic polymorphisms on the risk of developing alopecia areata: A systematic review of the literature and meta-analysis

Objectives Genetic association studies on alopecia areata (AA) performed in various populations have shown heterogeneous results. The aim of the current review was to synthesize the results of said studies to estimate the impact of FAS, FASL, PTPN22, CTLA4 and IL2RA gene polymorphisms on AA susceptibility. Design A systematic literature search was conducted in the Medline, Web of Science, Scopus, EMBASE and LILACS databases. Studies published up to June 2020 were included. The results available in the grey literature including the Open Grey and Google Scholar databases were also used. The texts of potentially related studies were screened by individual reviewers. Evidence of publication bias was assessed using the Newcastle-Ottawa scale and the quality of evidence was assessed using the GRADE system. The quantitative synthesis was performed using the fixed effect model. Results Out of 1784 articles, we identified 18 relevant articles for the qualitative synthesis and 16 for the quantitative synthesis. In a study of rs2476601 polymorphism of PTPN22 gene, including 1292 cases and 1832 controls, a correlation was found with the risk of developing AA in the allelic model (OR1.49 [95% C:1.13–1.95]), the heterozygous codominant (OR1.44 [95% CI:1:19–1.76]) and dominant model (OR1.43 [95% CI:1.18–1.73]). No association was found between the presence of FASL, PTPN22, CTLA and IL2RA gene polymorphisms with AA susceptibility. Conclusions The results suggest that the T allele of the single nucleoid polymorphism (SNP) rs2476601 in PTPN22 gene is a risk factor for developing alopecia areata. However, more robust studies defining the ethnic background of the population of origin are required, so that the risk identified in the present study can be validated. Additionally, a greater number of studies is necessary to evaluate the role of the FAS, FASL, PTPN22, CTLA4 and IL2RA genetic variants, given the heterogenous results found in the literature.