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The e4 allele of the apolipoprotein E gene represents the most widely reproduced and robust susceptibility loci for the most common late onset and sporadic forms of Alzheimer's disease. While the discovery of this now widely replicated association was reported more than 25 years ago, few therapeutic interventions that specifically target the apolipoprotein pathway in brain have emerged. Here we discuss our current understanding of apolipoprotein E biology in brain, its relationship to the pathogenesis of Alzheimer's disease and present potential future avenues for exploration that may be amenable to drug development.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Observational studies documented associations of NAFLD with several chronic and infectious diseases but whether these associations underlie causal effects is unknown. The molecular mechanisms and genetic architecture of NAFLD are poorly understood. Our objectives were to identify genetic loci associated with NAFLD and determine whether the presence of NAFLD was causally associated with human diseases. Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms (SNPs) associated with NAFLD in a meta-analysis of genome-wide association study (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted Mendelian Randomization (MR), we investigated the impact of NAFLD on human disease-related phenotypes in the UK Biobank and FinnGen cohorts as well as in the COVID-19 host genetics initiative. Results: We first performed a GWAS meta-analysis of four cohorts and found variants significantly associated with NAFLD (p800 diseases) using a genetic instrument for NAFLD. Results of these analyses suggest that NAFLD was not causally associated with diseases outside the spectrum of liver diseases. We also found no causal association between genetically predicted NAFLD and COVID-19-related outcomes. Conclusions: This study identified several new genetic loci associated with NAFLD. NAFLD was not causally associated with diseases outside those of the spectrum of liver diseases. This finding suggests that the resolution of NAFLD might not prevent other diseases previously associated with NAFLD.

Purpose Several lung cancer risk prediction models have been developed, but none to date have assessed the predictive ability of lung function in a population-based cohort. We sought to develop and internally validate a model incorporating lung function using data from the UK Biobank prospective cohort study. Methods This analysis included 502,321 participants without a previous diagnosis of lung cancer, predominantly between 40 and 70 years of age. We used flexible parametric survival models to estimate the 2-year probability of lung cancer, accounting for the competing risk of death. Models included predictors previously shown to be associated with lung cancer risk, including sex, variables related to smoking history and nicotine addiction, medical history, family history of lung cancer, and lung function (forced expiratory volume in 1 second [FEV1]). Results During accumulated follow-up of 1,469,518 person-years, there were 738 lung cancer diagnoses. A model incorporating all predictors had excellent discrimination (concordance (c)-statistic [95% CI] = 0.85 [0.82 to 0.87]). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected c-statistic = 0.84). The full model, including FEV1, also had modestly superior discriminatory power than one that was designed solely on the basis of questionnaire variables (c-statistic = 0.84 [0.82 to 0.86]; optimism-corrected c-statistic = 0.83; pFEV1 = 3.4 × 10−13). The full model had better discrimination than standard lung cancer screening eligibility criteria (c-statistic = 0.66 [0.64 to 0.69]). Conclusion A risk prediction model that includes lung function has strong predictive ability, which could improve eligibility criteria for lung cancer screening programs.

Background/Aims: To investigate the associations between the rs1250569 (zinc finger MIZ-type containing 1, ZMIZ1), rs1042522 (tumour protein p53, TP53), and rs10114470 (tumour necrosis factor-like cytokine 1A, TL1A) polymorphisms and the development of inflammatory bowel disease (IBD) in a Chinese (Han) population. We analysed the expression of genes that predispose patients to Crohn’s disease (CD) and ulcerative colitis (UC). Methods: A total of 381 IBD patients and 517 healthy controls were recruited into our study. Polymorphisms at the three loci were genotyped using polymerase chain reaction-ligation detection reactions (PCR-LDR). Genotype-phenotype correlations were analysed. Blood and gut samples were obtained and analysed using quantitative real-time PCR (qRT-PCR), western blot analysis, and immunohistochemistry to investigate the mRNA and protein levels and in situ expression of genes found to predispose patients to IBD. Furthermore, the expression of susceptible genes was further verified using a mouse dextran sulphate sodium (DSS)-induced acute colitis model. Results: No significant association was detected between rs1250569 and rs1042522 genotypes and CD or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls (55.03% vs. 48.48%, respectively; p = 0.044). The mutation rates at rs10114470 were dramatically lower at both the genotype and allele level in patients than those in healthy controls (p = 0.002 at both the genotype and allele level). Additionally, increased ZMIZ1 and TL1A levels were detected in intestinal samples obtained from both IBD patients and DSS-treated mice. Conclusion: rs1250569 (ZMIZ1) and rs10114470 (TL1A) are two novel loci that indicate susceptibility to IBD in Han-Chinese patients. Consistent with previous studies, TL1A expression levels were higher in Chinese Han IBD patients and DSS-treated mice. Most importantly, we found that ZMIZ1 expression was markedly higher in both IBD patients and mice with experimentally induced colitis, suggesting that ZMIZ1 plays important roles in the pathogenesis of IBD.

__Background:__ Whole genome array testing not only provides an increased diagnostic yield of pathogenic causative findings, but it may also reveal so called susceptibility loci (SL) for neurodevelopmental disorders. The goal of this study was to evaluate the pregnancy outcomes in SL cases and to establish a protocol for pregnancy management, follow-up and additional investigations. __Methods:__ Fifty seven cases were evaluated: 34 with and 23 without ultrasound anomalies at referral. Each pregnant couple received pretest counseling and extensive posttest genetic counseling. __Results:__ After diagnosis of SL, parental testing and an additional ultrasound examination were offered. The severity of the ultrasound anomalies and not the diagnosis of SL was the most important factor contributing to the decision on pregnancy continuation. In the majority of cases with milder or no ultrasound anomalies, the pregnancy was continued and a normal outcome after birth was observed. __Conclusions:__ The diagnosis of a SL did not seem to be a reason for termination of pregnancy. Most patients were able to cope with the uncertainty and were interested in both prenatal and postnatal actionability of SL. Long-term follow-up is crucial to assess the actual risks for neurodevelopmental disorders, especially in families with unremarkable history.

Late-onset Alzheimer's disease (AD), the most common neurodegenerative disorder in western countries, is clinically defined by progressive worsening in cognitive functions along with function and behavioral impairment. This ultimately results in complete incapacity and death. AD is a clinically and pathologically heterogeneous disease, and this is reflected by the numerous genetic findings that point to several diverse molecular mechanisms and pathways. Linkage, genome-wide association and next-generation sequencing studies have led to the identification of more than 20 novel susceptibility loci for AD. While these observations have significantly increased the knowledge of pathogenic mechanisms and potential therapeutic targets, a large part of the genetic component underlying AD is still unexplained. This review will summarize and discuss the major genetic findings and their potential impact on AD diagnosis and prediction of prognosis.

Recent studies have identified 10q24-rs17095355 as a susceptibility locus for biliary atresia (BA). To more precisely estimate the association between the rs17095355 polymorphism and BA risk, a meta-analysis was performed.A comprehensive search was conducted to examine all the eligible studies by electronic databases including Elsevier Science Direct, Pubmed, Google Scholar, China National Knowledge Infrastructure (CNKI) and Chinese Biomedical Literature (CBM) up to December 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association.A total of 6 comparisons from 5 relevant studies involving 1000 patients and 3257 controls were included to analyze the association between rs17095355 and BA risk. The pooled OR for T allele of rs17095355 was 1.72 (95%CI 1.53-1.92, p 0.01) in BA. Stratification by ethnicity indicated the degree of risk of rs17095355 with BA susceptibility was similar in populations of Asian origin. The pooled OR was 1.81 (95%CI 1.60-2.06, p 0.01).This meta-analysis confirms the association of rs17095355 polymorphism and BA development, especially in Asians. More original studies with large sample are needed to replicate this genetic association in different ethnic groups.

Xiao Jiang,1,2 Mei Zhang,3 Xiao-Yan Bai,1 Shujing Li,1 Huijian Wu1 1Laboratory of Molecular Medicine & Pharmacy, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, People’s Republic of China; 2Department of Gastroenterology, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, Heilongjiang University of Chinese Medicine, Haerbin, People’s Republic of China Background: Genome-wide association studies have identified rs6465657 polymorphism at chromosome 17q25.3 as a new prostate cancer (PCa) susceptibility locus in people of European descent. However, subsequent replication studies have yielded inconsistent results among different ethnicities. In this study, a comprehensive meta-analysis was conducted to systematically evaluate the relationship between rs6465657 polymorphism and PCa risk.Methods: All the articles involved were identified from PubMed, EMBASE, Web of Science, EBSCO databases, and Google Scholar before December 2015. The odds ratios (ORs) with corresponding 95% confidence internals (95% CIs) were pooled under the allele model. Fourteen eligible articles with 19 studies were finally included.Results: In the overall population, the 17q25.3-rs6465657C allele was found to be significantly associated with increased risk of PCa compared to the T allele (OR =1.097; 95% CI: 1.061–1.134; P

The term "fetal alcohol spectrum disorders" (FASD) defines the full range of ethanol (EtOH)-induced birth defects. Numerous variables influence the phenotypic outcomes of embryonic EtOH exposure. Among these variables, genetics appears to play an important role, yet our understanding of the genetic predisposition to FASD is still in its infancy. We review the current literature that relates to the genetics of FASD susceptibility and gene-EtOH interactions. Where possible, we comment on potential mechanisms of reported gene-EtOH interactions. Early indications of genetic sensitivity to FASD came from human and animal studies using twins or inbred strains, respectively. These analyses prompted searches for susceptibility loci involved in EtOH metabolism and analyses of candidate loci, based on phenotypes observed in FASD. More recently, genetic screens in animal models have provided an additional insight into the genetics of FASD. Understanding FASD requires that we understand the many factors influencing phenotypic outcome following embryonic EtOH exposure. We are gaining ground on understanding some of the genetics behind FASD, yet much work remains to be carried out. Coordinated analyses using human patients and animal models are likely to be highly fruitful in uncovering the genetics behind FASD.

Background Our previous study identified rs9387478 as a new susceptibility locus associated with lung cancer in never-smoking women in Asia; however, the clinical and prognostic significance of this finding is not known. Methods We analyzed the relationship between the rs9387478 single nucleotide polymorphism and i) clinical parameters and ii) overall survival time in 505 female nonsmoking lung cancer patients, using the chi-square test and Kaplan-Meier analysis with the log-rank test, respectively. We further established the epidermal growth factor receptor (EGFR) mutation status and assessed its association with rs9387478 genotypes as well as the efficacy of EGFR tyrosine kinase inhibitors. Results The frequency of the AA genotype was significantly higher in the EGFR-mutation-negative group than in the EGFR-mutation-positive group (32% vs. 16%, χ 2 = 13.025, p = 0.011). Patients with the CC genotype had a better overall survival time than patients with the AA/AC genotype (median survival time: 54.2 vs. 32.9 months, χ 2 = 4.593, p = 0.032). The distribution of rs9387478 genotypes differed according to the clinical disease stage. Conclusions This study indicates that the rs9387478 genotype was associated with overall survival in nonsmoking female patients with lung cancer, although it was not significant after adjusting for multiple testing. The identification of the location of the rs9387478 single nucleotide polymorphism in the genomic interval containing the DCBLD1 and ROS1 genes, together with the finding that the rs9387478 polymorphism correlates with EGFR mutation status, may have important implications for therapeutic approaches targeting EGFR or ROS1 in patients with lung cancer.

Background: To aim of the study was describe the growth of publications on genetic myopia and understand the current research landscape through the analysis of citation networks, as well as determining the different research areas and the most cited publications. Methods: The Web of Science database was used to perform the publication search, looking for the terms “genetic*” AND “myopia” within the period between 2009 and October 2020. The CitNetExplorer and CiteSpace software were then used to conduct the publication analysis. To obtain the graphics, the VOSviewer software was used. Results: A total of 721 publications were found with 2999 citations generated within the network. The year 2019 was singled out as a “key year”, taking into account the number of publications that emerged in that year and given that in 2019, 200 loci associated with refractive errors and myopia were found, which is considered to be great progress. The most widely cited publication was “Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia”, an article by Verhoeven et al., which was published in 2013. By using the clustering function, we were able to establish three groups that encompassed the different research areas within this field: heritability rate of myopia and its possible association with environmental factors, retinal syndromes associated with myopia and the genetic factors that control and influence axial growth of the eye. Conclusions: The citation network offers a comprehensive and objective analysis of the main papers that address genetic myopia. Sin financiación 4.141 JRC (2021) Q2, 72/175 Genetics and Heredity 1.032 SJR (2021) Q2, 110/347 Genetics No data IDR 2021 UEM

Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach. Methods: Data from five GWAS studies in women of African ancestry with a combined sample size of 9241 cases and 10192 controls were used to generate pooled breast cancer risk estimates in a fixed effect meta-analysis, and this served as the discovery dataset. Summary statistics from the GWAS conducted in European ancestry populations (Breast Cancer Association Consortium, 122977 cases and 105974 controls) served as the validation dataset. The variants that were associated with breast cancer risk at P < 0.01 in the GWAS of African ancestry were meta-analyzed with the GWAS in European ancestry. A locus was considered novel if the lead index variant was genome-wide significant (5 × 10−8) in the cross-ancestry meta-analysis and >500kb away from known breast cancer risk loci. Conditional on the lead index variants, we searched for additional signals in each locus using multivariable logistic regression. Analyses were done separately for ER-positive, ER-negative and overall breast cancer risk. Results: We discovered four novel loci for overall breast cancer risk (1p13.3, 5q31.1, 15q24, and 15q26.3) and two novel loci for ER-negative breast cancer (1q41 and 7q11.23) at the genome-wide significance level of P < 5 × 10−8. Three index single nucleotide polymorphism (SNPs) lie within introns of genes (KCNK2, C5orf56, and SIN3A) and the other index SNPs are located in intergenic regions (close to GSTM4 and AMPD2, CASTOR2, and the antisense DNA RP11-168G16.2). The direction of the associations was consistent between the GWASs of African and European descendants. At the 15q24 locus, we found an additional SNP (in the intron of the SCAMP2 gene) to be independently associated with overall breast cancer risk. Conclusions: We have identified six new risk loci that may contribute to better prediction of breast cancer risk in African ancestry populations and provide new insights into mechanisms of breast cancer carcinogenesis. Replication of these loci in multiple populations and functional studies can help to identify causal variants. Citation Format: Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, Dezheng Huo. Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4613.

International audience; In recent years, the introduction of novel genome analysis technologies (such as array comparative genomic hybridization) has enabled the prenatal diagnosis of various recurrent copy number variations (CNVs). Some of these CNVs have been linked to a greater susceptibility of developmental and neuropsychiatric disorders; for example, recurrent duplication at the 2q13 locus is associated with developmental delay, dysmorphism and intellectual disability. However, this CNV has low penetrance and variable clinical expressivity. It also can be observed in healthy controls and can be transmitted by unaffected parents, making genetic counseling especially challenging. Here, we report on the inheritance of a 2q13 duplication in an asymptomatic family; the case highlights the role of the family survey in genetic counseling with regard to novel CNVs diagnosed before birth.

Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in those of African Ancestry, but between 1 and 11% in all other 1000 Genomes populations. Recent research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions which impacted selection at its locus are synthesized to provide evidence for the TRPV6 haplotype as a germline susceptibility locus in cancer. Examination of a recently-proposed model for TRPV6 Ca2+-dependent inactivation, as it relates to the haplotype SNP identified as the target of selection, is proposed here as an explanatory mechanism for hypothesized failure to inactivate the channel at high Ca2+ concentrations in those who have the ancestral haplotype. This could result in an over-abundance of cellular Ca2+, which has been implicated in cancer, for those in settings where calcium dietary and supplemental intake is far higher than in their ancestral environment. This synthesis of recent research makes a case for investigation into the TRPV6 haplotype as a genomic factor in cancer disparity. If TRPV6 is found to be implicated, future research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African descent. Citation Format: Patricia Francis-Lyon, Fahreen Malik, Xiaoyun Cheng, Alireza Ghezavati, Feihan Xin, Rafiki Cai. TRPV6 as a putative genomic susceptibility locus influencing racial disparities in cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A069.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p, Translational Psychiatry, 9 (1), ISSN:2158-3188

Background: Intracranial atherosclerotic stroke is prevalent in Asians. We hypothesized patients with the Ring Finger protein 213 ( RNF213 ) variant, a susceptibility locus for moyamoya disease in East Asians, have different neuroimaging characteristics in terms of vessel wall and hemodynamics. Methods: We analyzed consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant plaque on the distal internal carotid artery or proximal MCA on high-resolution MRI (HR-MRI). Patients with carotid/cardiac sources of embolism or angiographic features of moyamoya disease were excluded. HR-MRI features (e.g., outer vessel diameters and plaque characteristics) and fractional flow (as measured by adjusted signal intensity ratio on time-of-flight MRA) were compared between RNF213 p.Arg4810Lys variant carriers and non-carriers. Results: Of 144 patients included, 44 (29.9%) patients had the RNF213 variant. Clinical characteristics including age, gender, and vascular risk factors were not different between RNF213 variant carriers and non-carriers. However, outer vessel diameter was smaller in RNF213 variant carriers than in non-carriers (p Conclusions: The RNF213 variant may be associated with vasculogenesis but not with atherogenesis. Patients with this variant had small intracranial arteries predisposing hemodynamic compromise in the presence of intracranial atherosclerosis. Beside anti-atherosclerotic strategies, further studies are warranted to develop a novel therapeutic strategies against RNF213 vasculopathy in Asians.

Nephrolithiasis is a common urological trait disorder with acute pain. Although previous studies have identified various genetic variations associated with nephrolithiasis, the host genetic factors remain largely unidentified. To identify novel nephrolithiasis loci in the Japanese population, we performed large-scale GWAS (Genome wide association study) using 11,130 cases and 187,639 controls, followed by a replication analysis using 2,289 cases and 3,817 controls. The analysis identified 14 significant loci, including 9 novel loci on 2p23.2-3, 6p21.2, 6p12.3, 6q23.2, 16p12.3, 16q12.2, 17q23.2, 19p13.12, and 20q13.2. Interestingly, 10 of the 14 regions showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic background among nephrolithiasis patients and these quantitative traits. Four novel loci are related to the metabolic pathway, while the remaining 10 loci are associated with the crystallization pathway. Our findings demonstrate the crucial roles of genetic variations in the development of nephrolithiasis.SIGNIFICANCE STATEMENTNephrolithiasis is a common urothelial disorders with frequent recurrence rate, but its genetic background is largely remained unidentified. Previous GWAS identified 6 genetic factors in total. Here we performed a GWAS using more than 200,000 samples in the Japanese populations, and identified 14 significant loci and nine of them are novel. We also found that 10 of the 14 loci showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (BMI, eGFR, UA, Ca etc). All 14 significant loci are associate with either metabolic or crystallization pathways. Thus, our findings elucidated the underlying molecular pathogenesis of nephrolithiasis.

The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13, 029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD., 特殊な網膜剥離の発症に関わる遺伝子変異を発見 --中心性漿液性脈絡網膜症のゲノムワイド関連解析--. 京都大学プレスリリース. 2019-12-13.

A genome-wide association study (GWAS) identified that BET1L rs2280543 at chromosome 11p15.5 was a susceptibility loci of intracranial aneurysm (IA). Long noncoding RNA H19, located in this region, was reported to play a crucial role in the formation of IA. In this study, we aimed to examine whether BET1L rs2280543 and potentially functional polymorphisms in H19 influence the risk of IA. A hospital-based case-control study was performed involving 542 IA patients and 588 age- and gender-matched controls. The BET1L rs2280543 and H19 polymorphisms were genotyped using the TaqMan assay. The BET1L rs2280543 CT, CT/TT genotypes, and T allele were associated with an increased risk of IA (CT vs. CC, adjusted OR=1.43, 95% CI: 1.08-1.90, P=0.01; CT/TT vs. CC, adjusted OR=1.48, 95% CI: 1.12-1.94, P=0.005; and T vs. C, adjusted OR=1.44, 95% CI: 1.13-1.83, P=0.003). Similarly, the H19 rs217727 TT genotype and T allele were associated with an increased risk of IA (TT vs. CC, adjusted OR=1.90, 95% CI: 1.35-2.67, P<0.001; T vs. C, adjusted OR=1.38, 95% CI: 1.16-1.64, P<0.001). Combined analyses revealed that the rs2280543 CC-rs217727 CT/TT, rs2280543 CT/TT-rs2735971 GG, and rs217727 CT/TT-rs2735971 GG genotypes were related to the risk of IA. Interaction analysis showed that the 3-loci model of rs2280543-rs217727-rs2839698 contributed to an increased risk of IA. These findings suggest that the GWAS-discovered risk loci BET1L rs2280543 may increase IA susceptibility by interacting with lncRNA H19.

In recent years, there has been an explosive increase in genetic studies related to autism spectrum disorder (ASD). This implicated the accumulation of a large amount of molecular data that may be used to verify various hypotheses and models developed to explore the complex genetic component of ASD. Several lines of evidence support the view that structural genomic variation contributes to the pathogenesis of ASD. The introduction of more sophisticated techniques for whole-genome screening, including array comparative genome hybridization and high-resolution single nucleotide polymorphism analysis, has allowed to identify an increasing number of ASD susceptibility loci. Copy number variants (CNVs) are the most common type of structural variation in the human genome and are considered important contributors to the pathogenesis of neurodevelopmental disorders, including ASD. In this review, we describe the accumulated evidence concerning the genetic events associated with ASD, and summarize current knowledge about the clinical relevance of CNVs in these disorders.

Contains fulltext : 203166.pdf (Publisher’s version ) (Open Access) The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.

Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.

Type 2 diabetes (T2D) and obesity are common chronic disorders with multifactorial etiology. In our study, we performed an exome sequencing analysis of 110 patients of Russian ethnicity together with a multi-perspective approach based on biologically meaningful filtering criteria to detect novel candidate variants and loci for T2D and obesity. We have identified several known single nucleotide polymorphisms (SNPs) as markers for obesity (rs11960429), T2D (rs9379084, rs1126930), and body mass index (BMI) (rs11553746, rs1956549 and rs7195386) (p &lt, 0.05). We show that a method based on scoring of case-specific variants together with selection of protein-altering variants can allow for the interrogation of novel and known candidate markers of T2D and obesity in small samples. Using this method, we identified rs328 in LPL (p = 0.023), rs11863726 in HBQ1 (p = 8 &times, 10&minus, 5), rs112984085 in VAV3 (p = 4.8 &times, 4) for T2D and obesity, rs6271 in DBH (p = 0.043), rs62618693 in QSER1 (p = 0.021), rs61758785 in RAD51B (p = 1.7 &times, 4), rs34042554 in PCDHA1 (p = 1 &times, 4), and rs144183813 in PLEKHA5 (p = 1.7 &times, 4) for obesity, and rs9379084 in RREB1 (p = 0.042), rs2233984 in C6orf15 (p = 0.030), rs61737764 in ITGB6 (p = 0.035), rs17801742 in COL2A1 (p = 8.5 &times, 5), and rs685523 in ADAMTS13 (p = 1 &times, 6) for T2D as important susceptibility loci in Russian population. Our results demonstrate the effectiveness of whole exome sequencing (WES) technologies for searching for novel markers of multifactorial diseases in cohorts of limited size in poorly studied populations.

To discover type 2 diabetes (T2D) loci and enhance fine-mapping resolution, we conducted the largest meta-analysis of genome-wide association studies of the disease to date by aggregating 171,262 cases and 1,075,072 controls from diverse populations (45% non-European ancestry). We identified 250 loci at genome-wide significance (p80% of the posterior probability of association (PPA); of these 35 signals had PPA of >99%. Clustering of signal-specific annotation enrichment highlighted distinct clades of T2D associations driven by different underlying molecular processes. These analyses represent the most comprehensive view of the genetic contribution to T2D to date and, through integration with expression quantitative trait loci in disease-relevant tissues, point to previously unreported effector genes (such as SKOR1, CLUAP1, and PEPD) and mediating molecular mechanisms at several loci. Disclosure H. Kitajima: None. X. Sim: None. M. Ng: None. W. Zhang: None. J.E. Below: None. A.J. Payne: None. K. Gaulton: None. A. Morris: None.

Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of ~50% by the age of 50; however, the known genes explain little of the heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases.

Zusammenfassung: Der Morbus Darier ist eine seltene Hauterkrankung, die autosomal-dominant vererbt wird und durch eine Mutation im SERCA (sarco/endoplasmatic reticulum calcium transporter)-2-Gen verursacht wird. In einigen Stammbäumen ist das Auftreten des Morbus Darier eng mit dem Vorkommen affektiver Erkrankungen verknüpft. Die wahrscheinlichste Ursache ist ein Suszeptibilitätsgen für affektive Erkrankungen in der Nähe des SERCA-2-Gens. Als Suszeptibilitätslokus konnte eine 6,5-Mb-Region identifiziert werden. Auch Studien mit affektiv erkrankten Stichproben, die nicht an Morbus Darier leiden, weisen ein Signal in der gleichen Region auf. Das zugrunde liegende Gen ist jedoch noch nicht identifiziert

Background Genetic factors play a prominent role in AS pathogenesis. So far over 40 non-MHC Ankylosing Spondylitis(AS) susceptibility loci with genome-wide or suggestive significance have been initially reported in Caucasians, however, lack of association evidence of most loci was seen in Chinese Han and some results seemed controversial. Objectives Here, we present a systematic evaluation of 47 non-MHC AS susceptibility loci using GWAS datasets in Chinese Han. Methods Totally 1853 AS cases and 4048 newly matched controls in 4 cohorts were obtained, after imputation meta-analysis results of 93 589 variants within 47 reported loci were extracted. Best-guess genotype data were used for interaction analysis and weighted genetic risk score model construction which was then assessed by receiver operator characteristic analysis. Functional annotation was conducted using HaploReg, RegulomeDB and rVarBase Database. Results We revealed 14 AS-associated variants with nominal evidence in Chinese Han, including rs10865331(p=2.96E-9), rs10050860 (p=1.84E-4) and rs8070463(p=2.81E-4) and found potential associated variants within these loci. We then extracted variants in ERAP1 as well as HLA-B27 tag snp rs13202464 for HLA-B27-ERAP1 interaction analysis (figure 1). Epistatic association between ERAP1 (rs30187, rs10045403) and HLA-B27 (rs13202464) was confirmed. Among those 14 variants, rs30187 showed weaker risk effect in Chinese while rs10050860 and rs12504282 seemed to attribute more risk (Table 1). Genetic prediction model combining 14 variants in 11 loci with HLA-B27 achieved better discrimination ability(AUC=0.884, 95%CI=0.873~0.895) than HLA-B27 alone(p=2.17E-6). We also identified some likely functional variants at these loci. Conclusions Our results provided a detailed spectrum of non-MHC AS susceptibility loci in Chinese Han and highlighted 2 p15, ERAP1 and TBKBP1 may play a critical role in AS pathogenesis. References [1] IGAS, Cortes A, Hadler J, et al. Nature genetics. 2013Jul; 45(7):730–738. [2] Ellinghaus D, Jostins L, Spain SL, et al. Nature genetics. 2016May; 48(5):510–518. Disclosure of Interest None declared

Some studies have demonstrated interactions of AD-risk single nucleotide polymorphisms (SNPs) in non-APOE regions with APOE genotype. Nevertheless, no study reported interactions of expression quantitative trait locus (eQTL) for APOE with APOE genotype. In present study, we included 9286 unrelated AD patients and 8479 normal controls from 12 cohorts of NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) and Alzheimer’s Disease Neuroimaging Initiative (ADNI). 34 unrelated brain eQTLs for APOE were compiled from BRAINEAC and GTEx. We used multi-covariate logistic regression analysis to identify eQTLs interacted with APOE ε4. Adjusted for age and gender, substantia nigra eQTL rs438811 for APOE showed significantly strong interaction with APOE ε4 status (OR, 1.448; CI, 1.124–1.430; P-value = 7.94 × 10−6). APOE ε4-based sub-group analyses revealed that carrying one minor allele T of rs438811 can increase the opportunity of developing to AD by 26.75% in APOE ε4 carriers but not in non-carriers. We revealed substantia nigra eQTL rs438811 for APOE can interact with APOE ε4 and confers risk in APOE ε4 carriers only.

Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.

Background/Objective: Recent genome wide association studies identified SLC44A2 as a novel susceptibility locus for venous thromboembolism (VTE), a region encoding the solute carrier family 44 member 2 protein (SLC44A2). Here we utilize Slc44a2 deficient mice (KO) to determine the importance of SLC44A2 in thrombotic disease. Methods: Mice lacking Slc44a2 were included in two models of venous thrombosis: 1) a spontaneous thrombosis model using siRNA targeting anti-coagulants Serpinc1 and Proc and 2) a model of deep vein thrombosis (DVT) induced by flow restriction (stenosis) of the inferior vena cava (IVC). Results: In the model of spontaneous thrombosis, Slc44a2 deficiency did not affect incidence as occurrence of thrombotic phenotype reached 100% in both wild type (WT; 12/12) and KO (12/12) mice 32 hours after siRNA injection. Platelet counts and fibrin deposition in the liver were also comparable. However, levels of circulating neutrophils were significantly higher (p=0.0017) in KO mice along with substantially lower amounts of plasma VWF antigen (pSlc44a2 did (12/15). Thrombus length was significantly reduced in KO animals (p=0.0184), as was thrombus weight (p=0.0413). Immunhistochemical staining of the thrombi revealed different repartitions in the “white” (platelet-rich) over the “red” (RBC-rich) parts of the thrombi depending on the mouse genotype. This observation suggests a different blood cell mobilization at the site of stenosis depending of the genotype. Plasma VWF levels were correlated with thrombus weight in WT (p=0.0175), but not in KO mice (p=0.3266), and had been previously confirmed to be lower in KO mice. Conclusion: These findings corroborate the original GWAS data, indicating a role for SLC44A2 in thrombotic disease. We have observed that SLC44A2 was not involved in a platelet-dependent model of thrombosis whereas it is involved in a thrombosis model where neutrophils and VWF have been shown to play a crucial role.

Objectives: To investigate the conditions and analysis strategies required so that endophenotypes related to a disease help discover genetic variants involved in the disease. Methods: The association with disease susceptibility variants is examined as a function of the relationships between disease status, endophenotype values and the genotype at another disease or endophenotype susceptibility locus assumed to be previously known, using approximate linear models of allele frequencies as a function of these variables and simulations in the context of family studies when the endophenotype is dichotomous. Results: Under genetic mechanisms where the risk allele of the tested locus has an effect exclusively in subjects with the endophenotype, the risk allele frequency differences between affected and unaffected subjects are much greater in the subset of subjects with an endophenotype impairment than in those without such an impairment, and power gains are obtained when testing the association under a joint disease-endophenotype model, both with two-locus or single-locus tests. However, with moderate main effect on the risk of disease or endophenotype impairment, testing directly the association between risk allele and disease or endophenotype is more powerful than testing under a joint disease-endophenotype model. Conclusions: Joint modeling of disease and endophenotype should be used only in parallel with standard disease association testing.

BACKGROUND Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of

Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have implicated specific pathways in the disease, in particular intracellular trafficking/endocytosis, inflammation and immune response and lipid metabolism. These observations have significantly advanced our understanding of underlying pathogenic mechanisms and potential therapeutic targets. This review article summarizes these recent advances in AD genomics and discusses the value of identified susceptibility loci for diagnosis and prognosis of AD.

Background Mutations or single nucleotide polymorphisms (SNPs) within the gene region of microRNAs play an important role for the development of hepatocellular carcinoma (HCC). Extensive studies have tried to investigate the susceptibility role of miR-146a rs2819164 and miR-196a-2 rs11614913. However, these results are still inconsistent and inconclusive. We undertook a meta-analysis containing primarily Asian studies to assess the associations of the two SNPs with HCC risk. Methods 19 studies including miR-146a (7170 cases and 9443 controls) and 15 studies including miR-196a-2 (6417 cases and 7627 controls) were used for meta-analysis. Odds ratios and 95% CI were calculated to assess the association in five different genetic models. Results For the rs2910164 polymorphism of miR-146a, significantly increased risks for HCC were observed when all studies were pooled under two models (CG vs CC: OR = 1.11, 95% CI = 1.02–1.21, P = 0.021; GG + CG vs CC: OR = 1.11, 95% CI = 1.01–1.22, P = 0.035). For the rs11614913 polymorphism of miR-196a-2, significant increased risks for HCC development were observed when all studies were pooled under four models (C vs T: OR = 1.14, 95% CI = 1.06–1.23, P = 0.001; CC vs TT: OR = 1.31, 95% CI = 1.12–1.53, P = 0.001; CC + TC vs TT: OR = 1.16, 95% CI = 1.03–1.31, P = 0.018; CC vs TC + TT: OR = 1.14, 95% CI = 1.00–1.30, P = 0.043). Conclusion Our results show that the two common SNPs within the miRNAs were associated with modest increased risk of HCC (OR

Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations.To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-ε4 status to eliminate the established effect of APOE region.Our data indicated that 18p11.32 (rs1992269, P = 9.77 × 10(-7)), CNTNAP2 (rs802571, P = 1.26 × 10(-6)), and 12q24.23 (rs11613092, P = 6.85 × 10(-6)) were suggestive loci for susceptibility to LOAD.We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.