Online Mendelian Inheritance in Animals (OMIA): a genetic resource for vertebrate animals.

Online Mendelian Inheritance in Animals (OMIA) is a freely available curated knowledgebase that contains information and facilitates research on inherited traits and diseases in animals. For the past 29 years, OMIA has been used by animal geneticists, breeders, and veterinarians worldwide as a definitive source of information. Recent increases in curation capacity and funding for software engineering support have resulted in software upgrades and commencement of several initiatives, which include the enhancement of variant information and links to human data resources, and the introduction of ontology-based breed information and categories. We provide an overview of current information and recent enhancements to OMIA and discuss how we are expanding the integration of OMIA into other resources and databases via the use of ontologies and the adaptation of tools used in human genetics.

Early diagnosis of immunodeficient patients with partial albinism: The role of hair study and peripheral blood smear.

BACKGROUND: Primary immunodeficiency diseases (inborn errors of immunity) with partial albinism are a group of autosomal recessive syndromes including Chediak Higashi Syndrome (CHS), Griscelli Syndrome type 2 (GS2), Hermansky-Pudlak Syndromes type 2 and 10 (HPS2, HPS10), Vici syndrome and P14/LAMTOR2 deficiency. METHODS: Twenty-five patients including 10 CHS, 10 GS2, and 5 HPS2 were evaluated in this study within the last 10 years. Five cases with oculocutaneous albinism (OCA) and 5 healthy subjects without albinism were used as two control groups. Genetic analyses were performed by whole exome or panel sequencing or targeted Sanger sequencing. Subsequently, leukocyte granules in peripheral blood smear and hair shaft were examined as screening tests. RESULTS: Giant granules were only presented in the leukocytes cytoplasm of 10/10 CHS patients. The uneven cluster of pigments and giant melanin granules in hair samples were observed in 10/10 GS2 and 10/10 CHS patients, respectively. In both 5/5 OCA and 5/5 HPS2 patients, there were regular pigments in the middle of hair shafts. Genetic analyses were performed for all patients, revealing 7 novel variants in LYST gene for CHS patients and 4 novel variants in AP3B1 for HPS2 patients. CONCLUSION: Receiving hematopoietic stem cell transplantation (HSCT) in a timely manner is crucial in CHS and GS2 patients; therefore, screening tests may provide a vital clue for early diagnosis in these patients. However, the final confirmation of CHS, GS2, and HPS2 disorders is done by genetic assay.

Genetic variation in histone modifications and gene expression identifies regulatory variants in the mammary gland of cattle.

BACKGROUND: Causal variants for complex traits, such as eQTL are often found in non-coding regions of the genome, where they are hypothesised to influence phenotypes by regulating gene expression. Many regulatory regions are marked by histone modifications, which can be assayed by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Sequence reads from ChIP-seq form peaks at putative regulatory regions, which may reflect the amount of regulatory activity at this region. Therefore, eQTL which are also associated with differences in histone modifications are excellent candidate causal variants. RESULTS: We assayed the histone modifications H3K4Me3, H3K4Me1 and H3K27ac and mRNA in the mammary gland of up to 400 animals. We identified QTL for peak height (histone QTL), exon expression (eeQTL), allele specific expression (aseQTL) and allele specific binding (asbQTL). By intersecting these results, we identify variants which may influence gene expression by altering regulatory regions of the genome, and may be causal variants for other traits. Lastly, we find that these variants are found in putative transcription factor binding sites, identifying a mechanism for the effect of many eQTL. CONCLUSIONS: We find that allele specific and traditional QTL analysis often identify the same genetic variants and provide evidence that many eQTL are regulatory variants which alter activity at regulatory regions of the bovine genome. Our work provides methodological and biological updates on how regulatory mechanisms interplay at multi-omics levels.

The statistical power of genome-wide association studies for threshold traits with different frequencies of causal variants.

This study aimed to investigate the effects of incidence rate, heritability, and polygenic variance on the statistical power of genome-wide association studies (GWAS) for threshold traits. Different incidence rates of threshold trait (1, 3, 5, 10, 25, 40, 50, 60, 75 and 90%), heritability (10 and 25%), and polygenic variance ratio (0 and 25%) were simulated separately for common (MAF ≥ 0.05), low-frequency (0.05 > MAF ≥ 0.01), and rare (MAF < 0.01) variants. Association studies were performed by logistic and linear mixed models. The highest statistical powers were observed in common and low-frequency variants with an incidence of 25-50% and 10-40%, respectively, but for rare variants, the highest statistical power was observed at low incidence. For all causal variant frequencies, the estimated heritability decline with an increase in incidence rate. We found high statistical power for traits with high heritability. In contrast, those with a high polygenic variance ratio have lower statistical power to detect common causal variants using a linear mixed model. These results demonstrate that the incidence rate of threshold traits, heritability, and polygenic variance may affect the statistical power of GWAS. Therefore, it is recommended that the effect of incidence rate, heritability, and polygenic variance be considered in designing GWAS for threshold traits.

Functional Allele Validation by Gene Editing to Leverage the Wealth of Genetic Resources for Crop Improvement.

Advances in molecular technologies over the past few decades, such as high-throughput DNA marker genotyping, have provided more powerful plant breeding approaches, including marker-assisted selection and genomic selection. At the same time, massive investments in plant genetics and genomics, led by whole genome sequencing, have led to greater knowledge of genes and genetic pathways across plant genomes. However, there remains a gap between approaches focused on forward genetics, which start with a phenotype to map a mutant locus or QTL with the goal of cloning the causal gene, and approaches using reverse genetics, which start with large-scale sequence data and work back to the gene function. The recent establishment of efficient CRISPR-Cas-based gene editing promises to bridge this gap and provide a rapid method to functionally validate genes and alleles identified through studies of natural variation. CRISPR-Cas techniques can be used to knock out single or multiple genes, precisely modify genes through base and prime editing, and replace alleles. Moreover, technologies such as protoplast isolation, in planta transformation, and the use of developmental regulatory genes promise to enable high-throughput gene editing to accelerate crop improvement.

Causal variants in Maturity Onset Diabetes of the Young (MODY) - A systematic review.

BACKGROUND: Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date. METHODS: We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes. RESULTS: The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries. CONCLUSIONS: We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.

Online Mendelian Inheritance in Animals (OMIA): a record of advances in animal genetics, freely available on the Internet for 25 years.

For the last 25 years, Online Mendelian Inheritance in Animals (OMIA) has been providing free global access to an ever-increasing record of discoveries made by animal geneticists around the world. To mark this 25-year milestone, this document provides a brief account (including some pre-history) of how OMIA came to be; some timelines of important discoveries and advances in the genetics of the animal species covered by OMIA, gleaned from the OMIA database; and an analysis of the current state of knowledge regarding likely causal variants of single-locus traits in OMIA species, also gleaned from the OMIA database.

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits.

Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10-7); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-trans-eGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the trans-eGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

Widespread Allelic Heterogeneity in Complex Traits.

Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%-23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R2 = 0.85, p = 2.2 × 10-16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.

Identification of deleterious and regulatory genomic variations in known asthma loci.

BACKGROUND: Candidate gene and genome-wide association studies have identified hundreds of asthma risk loci. The majority of associated variants, however, are not known to have any biological function and are believed to represent markers rather than true causative mutations. We hypothesized that many of these associated markers are in linkage disequilibrium (LD) with the elusive causative variants. METHODS: We compiled a comprehensive list of 449 asthma-associated variants previously reported in candidate gene and genome-wide association studies. Next, we identified all sequence variants located within the 305 unique genes using whole-genome sequencing data from the 1000 Genomes Project. Then, we calculated the LD between known asthma variants and the sequence variants within each gene. LD variants identified were then annotated to determine those that are potentially deleterious and/or functional (i.e. coding or regulatory effects on the encoded transcript or protein). RESULTS: We identified 10,130 variants in LD (r2 > 0.6) with known asthma variants. Annotations of these LD variants revealed that several have potentially deleterious effects including frameshift, alternate splice site, stop-lost, and missense. Moreover, 24 of the LD variants have been reported to regulate gene expression as expression quantitative trait loci (eQTLs). CONCLUSIONS: This study is proof of concept that many of the genetic loci previously associated with complex diseases such as asthma are not causative but represent markers of disease, which are in LD with the elusive causative variants. We hereby report a number of potentially deleterious and regulatory variants that are in LD with the reported asthma loci. These reported LD variants could account for the original association signals with asthma and represent the true causative mutations at these loci.

The genetic background of inflammatory bowel disease: from correlation to causality.

Recent studies have greatly improved our insight into the genetic background of inflammatory bowel disease (IBD). New high-throughput technologies and large-scale international collaborations have contributed to the identification of 200 independent genetic risk loci for IBD. However, in most of these loci, it is unclear which gene conveys the risk for IBD. More importantly, it is unclear which variant within or near the gene is causal to the disease. Using targeted GWAS, imputation, resequencing of risk loci, and in silico fine-mapping of densely typed loci, several causal variants have been identified in IBD risk genes, and various pathological pathways have been uncovered. Current research in the field of IBD focuses on the effect of these causal variants on gene expression and protein function. However, more elements than only the genome must be taken into account to disentangle the multifactorial pathology of IBD. The genetic risk loci identified to date only explain a small part of genetic variance in disease risk. Currently, large multi-omics studies are incorporating factors ranging from the gut microbiome to the environment. In this review, we present the progress that has been made in IBD genetic research and stress the importance of studying causality to increase our understanding of the pathogenesis of IBD. We highlight important causal genetic variants in the candidate genes NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1. We describe their downstream effects on protein function and their direct effects on the gut immune system. Furthermore, we discuss the future role of genetics in unravelling disease mechanisms in IBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The SSV Evaluation System: A Tool to Prioritize Short Structural Variants for Studies of Possible Regulatory and Causal Variants.

Short structural variants (SSVs) are short genomic variants (<50 bp) other than SNPs. It has been suggested that SSVs contribute to many human complex traits. However, high-throughput analysis of SSVs presents numerous technical challenges. In order to facilitate the discovery and assessment of SSVs, we have developed a prototype bioinformatics tool, "SSV evaluation system," which is a searchable, annotated database of SSVs in the human genome, with associated customizable scoring software that is used to evaluate and prioritize SSVs that are most likely to have significant biological effects and impact on disease risk. This new bioinformatics tool is a component in a larger strategy that we have been using to discover potentially important SSVs within candidate genomic regions that have been identified in genome-wide association studies, with the goal to prioritize potential functional/causal SSVs and focus the follow-up experiments on a relatively small list of strong candidate SSVs. We describe our strategy and discuss how we have used the SSV evaluation system to discover candidate causal variants related to complex neurodegenerative diseases. We present the SSV evaluation system as a powerful tool to guide genetic investigations aiming to uncover SSVs that underlie human complex diseases including neurodegenerative diseases in aging.

Detecting recent positive selection with high accuracy and reliability by conditional coalescent tree.

Studies of natural selection, followed by functional validation, are shedding light on understanding of genetic mechanisms underlying human evolution and adaptation. Classic methods for detecting selection, such as the integrated haplotype score (iHS) and Fay and Wu's H statistic, are useful for candidate gene searching underlying positive selection. These methods, however, have limited capability to localize causal variants in selection target regions. In this study, we developed a novel method based on conditional coalescent tree to detect recent positive selection by counting unbalanced mutations on coalescent gene genealogies. Extensive simulation studies revealed that our method is more robust than many other approaches against biases due to various demographic effects, including population bottleneck, expansion, or stratification, while not sacrificing its power. Furthermore, our method demonstrated its superiority in localizing causal variants from massive linked genetic variants. The rate of successful localization was about 20-40% higher than that of other state-of-the-art methods on simulated data sets. On empirical data, validated functional causal variants of four well-known positive selected genes were all successfully localized by our method, such as ADH1B, MCM6, APOL1, and HBB. Finally, the computational efficiency of this new method was much higher than that of iHS implementations, that is, 24-66 times faster than the REHH package, and more than 10,000 times faster than the original iHS implementation. These magnitudes make our method suitable for applying on large sequencing data sets. Software can be downloaded from https://github.com/wavefancy/scct.

Statistical testing of shared genetic control for potentially related traits.

Integration of data from genome-wide single nucleotide polymorphism (SNP) association studies of different traits should allow researchers to disentangle the genetics of potentially related traits within individually associated regions. Formal statistical colocalisation testing of individual regions requires selection of a set of SNPs summarising the association in a region. We show that the SNP selection method greatly affects type 1 error rates, with published studies having used methods expected to result in substantially inflated type 1 error rates. We show that either avoiding variable selection and instead testing the most informative principal components or integrating over variable selection using Bayesian model averaging can help control type 1 error rates. Application to data from Graves' disease and Hashimoto's thyroiditis reveals a common genetic signature across seven regions shared between the diseases, and indicates that in five of six regions associated with Graves' disease and not Hashimoto's thyroiditis, this more likely reflects genuine absence of association with the latter rather than lack of power. Our examination, by simulation, of the performance of colocalisation tests and associated software will foster more widespread adoption of formal colocalisation testing. Given the increasing availability of large expression and genetic association datasets from disease-relevant tissue and purified cell populations, coupled with identification of regulatory sequences by projects such as ENCODE, colocalisation analysis has the potential to reveal both shared genetic signatures of related traits and causal disease genes and tissues.

Comparing the efficacy of SNP filtering methods for identifying a single causal SNP in a known association region.

Genome-wide association studies have successfully identified associations between common diseases and a large number of single nucleotide polymorphisms (SNPs) across the genome. We investigate the effectiveness of several statistics, including p-values, likelihoods, genetic map distance and linkage disequilibrium between SNPs, in filtering SNPs in several disease-associated regions. We use simulated data to compare the efficacy of filters with different sample sizes and for causal SNPs with different minor allele frequencies (MAFs) and effect sizes, focusing on the small effect sizes and MAFs likely to represent the majority of unidentified causal SNPs. In our analyses, of all the methods investigated, filtering on the ranked likelihoods consistently retains the true causal SNP with the highest probability for a given false positive rate. This was the case for all the local linkage disequilibrium patterns investigated. Our results indicate that when using this method to retain only the top 5% of SNPs, even a causal SNP with an odds ratio of 1.1 and MAF of 0.08 can be retained with a probability exceeding 0.9 using an overall sample size of 50,000.

Review: Genetic mutations affecting bull fertility.

Cattle are a well-suited "model organism" to study the genetic underpinnings of variation in male reproductive performance. The adoption of artificial insemination and genomic prediction in many cattle breeds provide access to microarray-derived genotypes and repeated measurements for semen quality and insemination success in several thousand bulls. Similar-sized mapping cohorts with phenotypes for male fertility are not available for most other species precluding powerful association testing. The repeated measurements of the artificial insemination bulls' semen quality enable the differentiation between transient and biologically relevant trait fluctuations, and thus, are an ideal source of phenotypes for variance components estimation and genome-wide association testing. Genome-wide case-control association testing involving bulls with either aberrant sperm quality or low insemination success revealed several causal recessive loss-of-function alleles underpinning monogenic reproductive disorders. These variants are routinely monitored with customised genotyping arrays in the male selection candidates to avoid the use of subfertile or infertile bulls for artificial insemination and natural service. Genome-wide association studies with quantitative measurements of semen quality and insemination success revealed quantitative trait loci for male fertility, but the underlying causal variants remain largely unknown. Moreover, these loci explain only a small part of the heritability of male fertility. Integrating genome-wide association studies with gene expression and other omics data from male reproductive tissues is required for the fine-mapping of candidate causal variants underlying variation in male reproductive performance in cattle.

[Cellular and supracellular models in the study of molecular mechanisms associated with schizophrenia]. / Kletochnye i nadkletochnye modeli v izuchenii molekulyarnykh mekhanizmov, assotsiirovannykh s shizofreniei.

Schizophrenia is a severe mental illness, in the etiology and pathogenesis of which hereditary factors make a significant contribution. Studies of the genetic causes of schizophrenia are conducted using a variety of models. This brief review introduces the reader to cellular and supracellular models that, because of their simplicity, low cost, and low labor intensity, help to effectively investigate the complex molecular mechanisms associated with schizophrenia. The potential of cellular and supracellular models is greatly enhanced by the use of the CRISPR/Cas9 genome editing technology. Genetically modified models make it possible to achieve a previously inaccessible depth and detail of understanding of the role of genetic factors in the onset and development of schizophrenia. The information obtained can be used in the design of new drugs for personalized treatment of schizophrenia patients.

Causal Inference of Genetic Variants and Genes in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive multisystem disorder with limited therapeutic options. Although genome-wide association studies (GWASs) have revealed multiple ALS susceptibility loci, the exact identities of causal variants, genes, cell types, tissues, and their functional roles in the development of ALS remain largely unknown. Here, we reported a comprehensive post-GWAS analysis of the recent large ALS GWAS (n = 80,610), including functional mapping and annotation (FUMA), transcriptome-wide association study (TWAS), colocalization (COLOC), and summary data-based Mendelian randomization analyses (SMR) in extensive multi-omics datasets. Gene property analysis highlighted inhibitory neuron 6, oligodendrocytes, and GABAergic neurons (Gad1/Gad2) as functional cell types of ALS and confirmed cerebellum and cerebellar hemisphere as functional tissues of ALS. Functional annotation detected the presence of multiple deleterious variants at three loci (9p21.2, 12q13.3, and 12q14.2) and highlighted a list of SNPs that are potentially functional. TWAS, COLOC, and SMR identified 43 genes at 24 loci, including 23 novel genes and 10 novel loci, showing significant evidence of causality. Integrating multiple lines of evidence, we further proposed that rs2453555 at 9p21.2 and rs229243 at 14q12 functionally contribute to the development of ALS by regulating the expression of C9orf72 in pituitary and SCFD1 in skeletal muscle, respectively. Together, these results advance our understanding of the biological etiology of ALS, feed into new therapies, and provide a guide for subsequent functional experiments.

Beyond GWAS: from simple associations to functional insights.

Each human, when born, has slightly different DNA sequences, which make each of us unique. The variations in DNA sequences are called genetic variants. The primary aim of genome-wide association study (GWAS) is to detect associations between genetic variants and human phenotypes. Since GWAS focuses on germ-line variants, there is no reverse causation. Therefore, GWAS is one of the few tools that can assess the causality of human diseases. In the past 10 years, many large-scale GWAS have been conducted. Although the primary outputs of GWAS are just a series of statistics, its downstream analyses provided many insights beyond simple associations: the causal mechanisms for autoimmune diseases and shared etiology between diseases. Moreover, GWAS downstream analyses generated scores potentially helpful in predicting clinical outcomes of each patient. This review focuses on GWAS for autoimmune diseases and introduces significant achievements of its downstream analyses. We also provide future directions that potentially overcome current limitations. We restrict our discussion to common autoimmune diseases (e.g., rheumatoid arthritis) since rare Mendelian diseases possess distinct genetic etiologies and are not tested by GWAS.

Open problems in human trait genetics.

Genetic studies of human traits have revolutionized our understanding of the variation between individuals, and yet, the genetics of most traits is still poorly understood. In this review, we highlight the major open problems that need to be solved, and by discussing these challenges provide a primer to the field. We cover general issues such as population structure, epistasis and gene-environment interactions, data-related issues such as ancestry diversity and rare genetic variants, and specific challenges related to heritability estimates, genetic association studies, and polygenic risk scores. We emphasize the interconnectedness of these problems and suggest promising avenues to address them.