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The severity of COVID-19 disease is partly determined by host genetic factors that have been reported by GWAS. We evaluated nine previously reported genome-wide significant associations regardless of the disease severity in a representative sample from the population of Latvia. Our cohort consisted of 475 SARS-CoV-2 positive cases, from which 146 were hospitalized individuals and 2217 controls. We found three variants from Neanderthal introgression event at the 3p21.31 region to be significantly associated with increased risk of SARS-CoV-2 infection and hospitalization status. The strongest association was displayed by rs71325088 with Bonferroni adjusted P=0.007, OR=1.46 [95% CI 1.17-1.81]. We performed fine-mapping by exploring 1 Mb region at 3p21.31 locus and identified 9 SNPs with even lower p-values with the strongest association estimated for rs2191031 P=5e-05, OR = 1.40[CI 95% 1.19-1.64] located in the LZTFL1. We show clear replication of 3p.21.31 locus in an independent cohort which favors further functional investigation of leading variants.

OBJECTIVE Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings. METHODS Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3). RESULTS Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage. CONCLUSION HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views.

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.

ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Background: Upper gastrointestinal tract cancers are the leading causes of cancer-related deaths in Northwest China and they share many similarities in terms of histological type, risk factors, and...

ObjectivesThe present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).MethodsWe performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.ResultsWe identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets.ConclusionThis study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

Keratoconus is a common ocular disorder that causes progressive corneal thinning and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is a highly heritable characteristic that is associated with keratoconus. In this two-stage genome-wide association study (GWAS) of CCT, we identified a locus for CCT, namely STON2 rs2371597 (P = 2.32 × 10−13), and confirmed a significant association between STON2 rs2371597 and keratoconus development (P = 0.041). Additionally, strong STON2 expression was observed in mouse corneal epithelial basal cells. We also identified SMAD3 rs12913547 as a susceptibility locus for keratoconus development using predictive analysis with IBM’s Watson question answering computer system (P = 0.001). Further GWAS analyses combined with Watson could effectively reveal detailed pathways underlying keratoconus development., Yoshikatsu Hosoda et al. study the genetic basis for central corneal thickness (CCT) that is associated with keratoconus. They identify two susceptibility loci, STON2 rs2371597 and SMAD3 rs12913547, using two-step genome-wide association study (GWAS) and predictive analysis with IBM’s Watson question answering computer system, respectively.

Summary Pyrenophora teres f. teres and P. teres f. maculata are significant pathogens that cause net blotch of barley. An increased number of loci involved in P. teres resistance or susceptibility responses of barley as well as interacting P. teres virulence effector loci have recently been identified through biparental and association mapping studies of both the pathogen and host. Characterization of the resistance/susceptibility loci in the host and the interacting effector loci in the pathogen will provide a path for targeted gene validation for better‐informed release of resistant barley cultivars. This review assembles concise consensus maps for all loci published for both the host and pathogen, providing a useful resource for the community to be used in pathogen characterization and barley breeding for resistance to both forms of P. teres., Pyrenophora teres causes net blotch of barley. Here we review the latest progress on host resistance and pathogen virulence, providing a valuable resource for the barley net blotch research community.

Diabetes is a major cause of mortality worldwide. There are several types of diabetes, with type 2 diabetes mellitus (T2DM) being the most common. Many factors, including environmental and genetic factors, are involved in the etiology of the disease. Numerous studies have reported the role of genetic polymorphisms in the initiation and development of T2DM. While genome-wide association studies have identified around more than 200 susceptibility loci, it remains unclear whether these loci are correlated with the pathophysiology of the disease. The present review aimed to elucidate the potential genetic mechanisms underlying T2DM. We found that some genetic polymorphisms were related to T2DM, either in the form of single-nucleotide polymorphisms or direct amino acid changes in proteins. These polymorphisms are potential predictors for the management of T2DM.

Introduction: Bone density disorders are characterized by a reduction in bone mass density and strength, which lead to an increase in the susceptibility to sudden and unexpected fractures. Despite the serious consequences of low bone mineral density (BMD) and its significant impact on human health, most affected individuals may not know that they have the disease because it is asymptomatic. Therefore, understanding the genetic basis of low BMD and osteoporosis is essential to fully elucidate its pathobiology and devise preventative or therapeutic approaches. Materials and Methods: we sequenced the whole genomes of 3000 individuals from the Qatar Biobank and conducted genome-wide association analyses to identify genetic risk factors associated with low BMD in the Qatari population. Results: Fifteen variants were significantly associated with total body BMD (p < 5 × 10-8). Of these, five variants had previously been reported by and were directionally consistent with previous genome-wide association study data. Ten variants were new: six intronic variants located at six gene loci (MALAT1/TALAM1, FASLG, LSAMP, SAG, FAM189A2, and LOC101928063) and four intergenic variants. Conclusion: This first such study in Qatar provides a new insight into the genetic architecture of low BMD in the Qatari population. Nevertheless, more studies are needed to validate these findings and to elucidate the functional effects of these variants on low BMD and bone fracture susceptibility.

Introduction: The low-density lipoprotein receptor-related protein 1 (LRP1), an endocytic receptor highly expressed in smooth muscle cells (SMCs), participates in diverse biological processes. A common genetic variant located in LRP1 first intron, rs11172113, was associated with several vascular diseases, including coronary artery disease, migraine and spontaneous coronary artery dissection, as well asd with LRP1 expression in arterial tissues. However, the biological mechanisms through which rs11172113 influence LRP1 function in the context of arterial lesions is not fully understood. Methods: We applied in silico functional annotation to select variants and measured their enhancer activity using luciferase reporter assay in rat primary cells (A7r5). We performed siRNA knockdown of LRP1 and 4 transcription factors (TFs) predicted to interact with rs11172113 in human induced pluripotent stem cells (iPSCs) derived SMCs. We analyzed both contractile (CSMCs) and synthetic (SSMCs) differentiated cells. We edited iPSCs prior to differentiation using CRISPR-Cas9 to generate 100 bp deletion of the enhancer region containing rs11172113. We also created frame-shift indels in exons 2 or 5 of LRP1 in iPSCs to create SMCs knockouts. Results: Seven variants in LRP1 locus co-located with enhancer (histone marks) and open chromatin regions (ATAC-Seq peaks) in SMCs and arterial tissues. Reporter assay in rat SMCs confirmed that rs11172113 belongs to a genomic region showing enhancer activity in vitro . iPSCs with homozygous deletion of rs11172113 enhancer region presented the same pluripotency compared with wild type, and iPSC derived SMCs showed positive expression of specific markers for each phenotype. We found that the deletion of enhancer region decreased the expression of LRP1 in both CSMCs and SSMCs. LRP1 knockdown decreased SSMCs and CSMCs proliferation capacity, but increased cell migration. Knockdown of TFs and iPSCs derived CSMCs and SSMCs with LRP1 knockout are currently under assessment. Conclusions: We confirmed rs11172113 to regulate LRP1 expression in iPSCs derived synthetic and contractile SMCs. Our results support LRP1 effect on SMCs phenotype alteration as a potential mechanism in genetic susceptibility for vascular disease.

Background The genetic substrate for headache in the general population has not been identified in Asians. We investigated susceptible genetic variants for self-reported headache in a large community-based Asian population. Methods We conducted a genome-wide association study in participants recruited from a community-based cohort to identify the genetic variants associated with headache in Taiwanese. All participants received a structured questionnaire for self-reported headache. A total of 2084 patients with “self-reported headache” and 11,822 age- and sex-matched controls were enrolled. Gene enrichment analysis using the Genotype-Tissue Expression version 6 database was performed to explore the potential function of the identified variants. Results We identified two novel loci, rs10493859 in TGFBR3 and rs13312779 in FGF23, that are functionally relevant to vascular function and migraine to be significantly associated with self-reported headache after adjusting age, sex and top 10 principal components ( p = 8.53 × 10−11 and p = 1.07 × 10−8, respectively). Gene enrichment analysis for genes with GWAS suggestive significance ( p −6) demonstrated that the expression of these genes was significantly enriched in the artery ( p = 8.18 × 10−4) and adipose tissue ( p = 8.95 × 10−4). Conclusion Our results suggest that vascular dysfunction might play important roles in the pathogenesis of self-reported headache in Asian populations.

Background The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. Methods We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. Findings We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. Interpretation We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia. Funding The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Objective: The purpose of this study was to investigate associations between the 14 reported loci (from a meta-analysis of genome-wide association studies [GWAS] in the Caucasian population) and vi...

Genetic alleles that contribute to enhanced susceptibility or resistance to viral infections and virally induced diseases have often been first identified in mice before humans due to the significant advantages of the murine system for genetic studies. Herein we review multiple discoveries that have revealed significant insights into virus-host interactions, all made using genetic mapping tools in mice. Factors that have been identified include innate and adaptive immunity genes that contribute to host defense against pathogenic viruses such as herpes viruses, flaviviruses, retroviruses, and coronaviruses. Understanding the genetic mechanisms that affect infectious disease outcomes will aid the development of personalized treatment and preventive strategies for pathogenic infections.

Gallstone disease is a common complex disease that confers a substantial economic burden on society. The genetic underpinnings of gallstone disease remain incompletely understood. We aimed to identify genetic associations with gallstone disease using publicly available data from the UK Biobank and two large Danish cohorts. We extracted genetic associations with gallstone disease from the Global Biobank Engine (GBE), an online browser of genome-wide associations in UK Biobank participants (14,940 cases and 322,268 controls). Significant associations (P 2.5 (prevalence 1%) had a 5-fold increased risk of gallstones compared to those with a score

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Objectives: To assess the feasibility and uptake of a community‐based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. Subjects and Methods: Healthy males aged 55–69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. Results: Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low‐risk and were managed with active surveillance. Conclusion: The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary: What is the paper about?: Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients?: We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large‐scale population prostate cancer screening.

Background: Genome-wide association studies (GWAS) have succeeded in identifying over 200 susceptibility loci for multiple sclerosis (MS). However, the potential functional variants and the mechanisms by which these loci affect MS risk remain largely unexplained. Objectives: We used summary data-based Mendelian randomisation to prioritise risk genes and infer potential biological mechanisms for MS risk loci. Methods: The data used consisted of DNA methylation ( n = 1980) QTL (mQTL) and gene expression ( n = 31,684) QTL (eQTL) derived from whole blood as well as MS GWAS summary statistics (14,802 cases, 26,703 controls). The findings were further evaluated using data derived from independent brain mQTL ( n = 1160) and eQTL ( n = 1194). Results: In whole blood, we identified two independent genomic loci (lincRNA: RP11-326C3.13 and TNFSF14) with consistent genome-wide significant pleiotropic associations across different omics layers. In brain tissue, a similar effect for the RP11-326C3.13 locus was observed but not for TNFSF14, indicating a potential tissue-specific effect for the TNFSF14 locus. Conclusion: We provide in silico evidence for the putative biological mechanisms by which the identified DNA methylation sites and target genes are functionally relevant to MS development in different tissues. Future research targeting these genes and DNA methylation sites will determine their roles in the pathophysiology of MS.

PURPOSE OF REVIEW Chromosomal-microarray analysis (CMA) is the first-tier test in pregnancies with structural malformations. Accumulating data show that pathogenic copy number variants (CNVs) can also be identified in structurally normal fetuses. We set out to summarize the published data on the diagnostic yield of CMA in structurally normal fetuses. RECENT FINDINGS Six studies summarize a total of 29,612 prenatal CMAs performed in structurally normal fetuses. The incidence of highly penetrant pathogenic/likely pathogenic CNVs is 0.4-2.5%. Variability was demonstrated in the timing of CMA testing and type of CNVs classified as pathogenic. The incidence of variants of uncertain significance is 0.4-5.4%. The prevalence of susceptibility loci is 0.3-0.7% when specified, and the incidence of CNVs associated with late onset disease is 0.1%. SUMMARY With a frequency of abnormal CNVs of 1:40 to 1:250 in structurally normal fetuses, it is recommended that all pregnant women be informed of the possibility to have CMA performed, even in the absence of malformations. Information should also be provided about uncertain and secondary findings.

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we show that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. This is the first demonstration of interaction between genetic factors in the human genome and the dysbiosis of gut microbiome in PD.

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in the Asian populations. To identify novel genetic loci associated with resistant hypertension in the Japanese population, we conducted a genome-wide association study with 2,705 resistant hypertension cases and 21,296 mild hypertension controls, all from BioBank Japan. We identified one novel susceptibility locus, rs1442386 on chromosome 18p11.3 (DLGAP1), achieving genome-wide significance (odds ratio (95% CI) = 0.85 (0.81–0.90), P = 3.75 × 10−8) and 17 loci showing suggestive association, including rs62525059 of 8q24.3 (CYP11B2). We further detected biological processes associated with resistant hypertension, including chemical synaptic transmission, regulation of transmembrane transport, neuron development and neurological system processes, highlighting the importance of the nervous system. This study provides insights into the etiology of resistant hypertension in the Japanese population.

Background Aortic stenosis (AS) is the most common form of incident valvular heart disease. While valve replacement is effective, the absence of an approved medical therapy provides no alternatives to patients with contraindications or mild disease. An improved understanding of the genetics of AS could identify targets for pharmacological intervention. Methods An inverse variance-weighted, fixed effects meta-analysis of the association of 11,591,806 variants with AS was undertaken using data from 10 European cohorts totalling 652,134 participants (13,758 cases of AS). We queried publicly available datasets to characterize the functional consequences of genome-wide significant variants, conducted a phenome-wide association study to assess their association with other outcomes, and constructed polygenic risk scores to examine their association with AS. We also performed gene- and gene-set enrichment analyses, estimated genetic correlation with cardiovascular traits, and assessed whether five lipid or immunological biomarkers were causally associated with AS using Mendelian randomization. Results Eighteen independent variants at 16 loci attained genome-wide significance in the meta-analysis, including variants at all seven previously reported loci. Many of the significant variants were intronic or intergenic, and the phenome-wide association study revealed extensive pleiotropy with apolipoprotein B, C-reactive protein, and other cardiovascular and immunological traits. A weighted polygenic risk score composed of the 18 variants was strongly associated with AS (adjusted OR per SD, 1.38; 95% CI, 1.33 to 1.44; p=4.6×10–57), and improved the discriminatory ability for AS when added to a model that contained clinical risk factors (difference in the area under the curve p=2.0×10–11). Gene-based approaches indicated higher IL6R expression in the blood among AS cases compared to controls (p=3.1×10–6), and the association of LDLR with AS (p=2.3×10–10). Gene set analyses revealed that genes bound by the transcription factor TCF7 or micro-RNAs miR-21, miR-219, miR-491, and miR-19 were differentially expressed in the liver depending on AS status (p≤5.7×10–4), suggesting disease development may be mediated by tissue-specific transcriptional and post-transcriptional regulation. Mendelian randomization supported a causal association of five lipid and immunological biomarkers with AS, including low-density lipoprotein cholesterol (OR per mmol/L, 1.61; 95% CI, 1.48 to 1.75; p=1.3×10–30). Conclusions Evidence from large-scale genetic analyses indicate that lipid metabolism, inflammation, and calcification are key contributors to AS. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Canadian Institutes of Health Research, National Institutes of Health

Background The heritability of Type 2 diabetes mellitus (T2DM) has been estimated to be 50% to 60%. Although genome-wide association studies identified >120 loci that confer susceptibility to T2DM, these studies were commonly conducted in a cross-sectional manner. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to T2DM in Japanese. We have now performed longitudinal exome-wide association studies (EWASs) to identify novel loci for T2DM by examining temporal changes in fasting plasma glucose (FPG) level, blood hemoglobin A1c (HbA1c) content, and the prevalence of T2DM. Methods Longitudinal EWASs (mean follow-up period, 5 years) were performed with Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip arrays and with 6,022 Japanese (755 subjects with T2DM, 5267 controls). The relation of genotypes of 24,579 SNPs that passed quality control to FPG level, blood HbA1c content, or the prevalence of T2DM was examined with the generalized estimating equation (GEE). To compensate for multiple comparisons of genotypes with each of the three parameters, we applied Bonferroni's correction for statistical significance of association. Results Longitudinal EWASs (GEE with adjustment for age, sex, body mass index, and smoking) revealed that rs6414624 of EVC (P Conclusion We have newly identified EVC and GGA3 as susceptibility loci for T2DM in Japanese. Determination of genotypes for these SNPs at these loci may prove informative for assessment of the genetic risk for T2DM in Japanese. Funding Acknowledgement Type of funding source: None

The clustered protocadherins (cPcdhs) are a subfamily of type I single-pass transmembrane cell adhesion molecules predominantly expressed in the brain. Their stochastic and combinatorial expression patterns encode highly diverse neural identity codes which are central for neuronal self-avoidance and non-self discrimination in brain circuit formation. In this review, we first briefly outline mechanisms for generating a tremendous diversity of cPcdh cell-surface assemblies. We then summarize the biological functions of cPcdhs in a wide variety of neurodevelopmental processes, such as neuronal migration and survival, dendritic arborization and self-avoidance, axonal tiling and even spacing, and synaptogenesis. We focus on genetic, epigenetic, and 3D genomic dysregulations of cPcdhs that are associated with various neuropsychiatric and neurodevelopmental diseases. A deeper understanding of regulatory mechanisms and physiological functions of cPcdhs should provide significant insights into the pathogenesis of mental disorders and facilitate development of novel diagnostic and therapeutic strategies.

Background Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia. Methods In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). Results PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04–2.54) and rs946961*CC (OR = 5.17, 95% CI: 1.20–22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR = 0.53, 95% CI: 0.29–0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one. Conclusions Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia.

Background Breast cancer is classified as one of the common cancers among women worldwide. Within numerous genetic factors involved in the development of breast cancer, lsp1 and casc genes are both located on breast cancer susceptibility locus. While the SNP rs3817198 in lsp1 gene has a twilight association with breast cancer in different populations, casc rs4784227 polymorphisms have been reported to associate with breast tumor appearance in Asian, European, and African ancestry populations. The present report was designed a case-control group aimed at assessing the association of these two SNPs with breast cancer risk in the Iranian population. Methods In the case-control study of rs3817198 and rs4784227 polymorphisms in 100 women with breast cancer and 100 healthy women were examined by Tetra Arms PCR. Data collected using SPSS software and chi-square test and correlation coefficient were used for statistical analysis. Results The results of current study showed that the Chi-square of lsp1 rs3817198 and casc rs4784227 polymorphism genotypes in breast cancer, were reported to be 51.613 and 47.920, respectively. Also there has been a significance level of both polymorphisms resulting in the frequency of genotypes in these two polymorphisms between case and control group. Conclusion Our finding thus suggested that in both polymorphisms, homozygote genotype showed strong correlation with cancer susceptibility. While, TT genotype in lsp1 rs3817198 showed significant association with pathogenic properties, in the case of casc rs4784227 genotypes CC, and in second place, TT showed similar correlation.

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.