Abstract 048: Association Analyses of up to ∼263,000 Individuals Provide New Insights into the Biology and Genetic Architecture of the Extremes of Anthropometric Traits

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Erik Ingelsson ◽  
Reedik Mägi ◽  
Stefan Gustafsson ◽  
Andrea Ganna ◽  
Eleanor Wheeler ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Architecture ◽  
Class Ii ◽  
Overweight And Obesity ◽  
European Ancestry ◽  
Continuous Measure ◽  
Phenotypic Variance ◽  
Obesity Class ◽  
Genome Wide ◽  
Meta Analyses

Anthropometric traits have a strong genetic component with heritability estimates between 40–70% for body mass index (BMI) and ∼80% for height; however, established loci only account for a small fraction (1–10%) of the phenotypic variance of these complex traits. It has been hypothesized that the extremes of the distributions of these traits are enriched for genetic loci and may have a distinct genetic architecture compared to the general population. To explore the genetic contribution of the extremes (defined as the upper and lower 5th percentile) of BMI, height, and waist-hip ratio [WHR] adjusted for BMI and clinical classes of obesity (including overweight and obesity classes I, II, and III), we conducted meta-analyses of ∼2.8 million SNPs from 49 genome-wide association studies of European ancestry totaling from 4,774 cases and 5,481 controls (extreme WHR) to 93,015 cases and 65,840 controls (overweight) for these traits. The most promising loci from each meta-analysis (P<5 x 10 −6 ) were taken forward for replication into up to 65,332 cases and 39,294 controls. In meta-analyses of the combined stages, we observed genome-wide significant associations (P<5 x 10 −8 ) for 191 loci (extreme BMI, height and WHR: 10, 96 and 2 loci, respectively; overweight and obesity classes I, II, and III: 25, 33, 24 and 1 loci, respectively). Out of these 191 loci, we identified 9 novel loci that have not been previously associated with anthropometric traits when studying the whole distributions (P<5 x 10 −8 ), including three loci for extreme height ( ZNF36, H6PD , RSRC1 ), three for obesity class II ( OLFM4 , HS6ST3 , AK5/ZZZ3 ), two for obesity class I ( GNAI3/MIR197/GNAT2, HNF4G ), and two for overweight ( RPTOR, HNF4G ). Several loci for obesity were located near genes expressed primarily in the brain (e.g. CACNA1D, AK5 ), suggesting a neuronal influence, whereas the loci for overweight were near genes involved in other processes, such as mTOR signaling (e.g. RPTOR ). All of the novel loci discovered for the extremes and obesity classes were nominally associated with the trait as a continuous measure in the general population (N = 123,865) but at a lesser significance level (P range: 0.003 – 1.4x10 −5 ). A polygenetic risk score including all independent SNPs associated with BMI (at different P-value thresholds) revealed that significantly more of the variance was explained for the extremes of BMI and obesity class II, than for BMI as a continuous measure in the population (variance explained, 20%, 10% and 5%, respectively), suggesting a greater genetic influence on the extremes. Investigations are underway to evaluate haplotypes and additional signals at known BMI and height loci in the extreme samples to explore allelic heterogeneity. In conclusion, this study identifies additional loci and provides novel insights into the genetic architecture of the extremes of anthropometric traits.

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
James S Floyd ◽  
Colleen Sitlani ◽  
Christy L Avery ◽  
Eric A Whitsel ◽  
Leslie Lange ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Qt Interval ◽  
Association Studies ◽  
Meta Analysis ◽  
Small Sample ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

scholarly journals Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke

2020 ◽  
Author(s):  
Laura Ibanez ◽  
Laura Heitsch ◽  
Caty Carrera ◽  
Fabiana H.G. Farias ◽  
Rajat Dhar ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Genetic Study ◽  
Genetic Architecture ◽  
Stroke Onset ◽  
Neurological Deficits ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Synaptic Protein ◽  
Genome Wide

ABSTRACTDuring the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a pre-synaptic protein, and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.RESEARCH INTO CONTEXTEvidence before this studyNo previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this studyThis is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidenceThe findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.

scholarly journals Genome-wide association study reveals the genetic architecture of 27 yield-related traits in tomato

2020 ◽  
Author(s):  
Jie Ye ◽  
Xin Wang ◽  
Wenqian Wang ◽  
Huiyang Yu ◽  
Guo Ai ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Genetic Research ◽  
Reproductive Development ◽  
Genome Wide Association ◽  
Phenotypic Variance ◽  
Vegetable Crop ◽  
Genome Wide ◽  
Malate Transporter

Abstract Tomato (Solanum lycopersicum) is a highly valuable vegetable crop and yield is one of the most important traits. Uncovering the genetic architecture of yield-related traits in tomato is critical for the management of vegetative and reproductive development, thereby enhancing yield. Here we perform a comprehensive genome-wide association study for 27 yield-related traits in tomato. A total of 239 significant associations corresponding to 129 loci, harboring many reported and novel genes related to vegetative and reproductive development, were identified, and these loci explained an average of ~8.8% of the phenotypic variance. A total of 51 loci associated with 25 traits have been under selection, especially during tomato improvement. Furthermore, a candidate gene, SlALMT15 that encodes an aluminum-activated malate transporter, was functionally characterized and shown to act as a pivotal regulator of leaf stomata formation through increasing photosynthesis and drought resistance. This study provides valuable information for tomato genetic research and breeding.

scholarly journals Localizing components of shared transethnic genetic architecture of complex traits from GWAS summary data

2019 ◽  
Author(s):  
Huwenbo Shi ◽  
Kathryn S. Burch ◽  
Ruth Johnson ◽  
Malika K. Freund ◽  
Gleb Kichaev ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Empirical Bayes ◽  
Genetic Correlations ◽  
Causal Snps ◽  
European Ancestry ◽  
Risk Scores ◽  
Common Snps ◽  
Genome Wide ◽  
Summary Data

AbstractDespite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. We analyze 9 complex traits in individuals of East Asian and European ancestry, restricting to common SNPs (MAF > 5%), and find that most common causal SNPs are shared by both populations. Using the genome-wide estimates as priors in an empirical Bayes framework, we perform fine-mapping and observe that high-posterior SNPs (for both the population-specific and shared causal configurations) have highly correlated effects in East Asians and Europeans. In population-specific GWAS risk regions, we observe a 2.8x enrichment of shared high-posterior SNPs, suggesting that population-specific GWAS risk regions harbor shared causal SNPs that are undetected in the other GWAS due to differences in LD, allele frequencies, and/or sample size. Finally, we report enrichments of shared high-posterior SNPs in 53 tissue-specific functional categories and find evidence that SNP-heritability enrichments are driven largely by many low-effect common SNPs.

scholarly journals Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes

2019 ◽  
Vol 22 (6) ◽  
pp. 900-909 ◽  
Author(s):  
Jingchun Chen ◽  
Anu Loukola ◽  
Nathan A Gillespie ◽  
Roseann Peterson ◽  
Peilin Jia ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Nicotine Dependence ◽  
Meta Analysis ◽  
Mapk Signaling ◽  
European Ancestry ◽  
Effective Prevention ◽  
Network Analyses ◽  
Chemokine Signaling ◽  
Genome Wide ◽  
Meta Analyses

Abstract Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. Conclusions Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. Implications Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

scholarly journals Combined analysis of keratinocyte cancers identifies novel genome-wide loci

2019 ◽  
Vol 28 (18) ◽  
pp. 3148-3160 ◽  
Author(s):  
Upekha E Liyanage ◽  
Matthew H Law ◽  
Xikun Han ◽  
Jiyuan An ◽  
Jue-Sheng Ong ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Association Studies ◽  
Genetic Correlations ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multiple Trait ◽  
Total N ◽  
Risk Variants ◽  
Genome Wide ◽  
Meta Analyses

Abstract The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

O-116 Genetic association analyses identify links between pelvic prolapse (PP) and connective tissue biology, cardiovascular and reproductive health

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
N Pujol Gualdo ◽  
K Läll ◽  
M Lepamets ◽  
R Arffman ◽  
T Piltonen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Meta Analyses ◽  
Personalized Risk

Abstract Study question Can genome-wide association analysis unravel the biological underpinnings of PP and facilitate personalized risk assessment via genetic risk scores construction? Summary answer We unravel novel links with urogenital development and vascular health in PP and present polygenic risk score as a tool to stratify PP risk. What is known already Prolapse is characterized by a descent of the pelvic organs into the vaginal cavity. PP affects around 40% of women after menopause and is the main indication for major gynecological surgery, having an important health, social and economic burden. Although the etiology and biological mechanisms underlying PP remain poorly understood, prior studies suggest genetic factors might play a role. Recently, a genome-wide association study (GWAS) identified seven genome-wide significant loci, located in or near genes involved in connective tissue metabolism and estrogen exposure in the etiology of PP. Study design, size, duration We conducted a three-stage case-control genome-wide association study. Firstly, in the discovery phase, we meta-analyzed Icelandic, UK Biobank and the FinnGen R3 datasets, comprising a total of 20118 cases and 427426 controls of European ancestry. For replication we used an independent dataset from Estonian Biobank (7968 cases and 118895 controls). Finally, we conducted a joint meta-analysis, containing 28086 cases and 546321 controls, which is the largest GWAS of PP to date. Participants/materials, setting, methods We performed functional annotation on genetic variants unraveled by GWAS and integrated these with expression quantitative trait loci and chromatin interaction data. In addition, we looked at enrichment of association signal on gene-set, tissue and cell type level and analyzed associations with other phenotypes both on genetic and phenotypic level. Colocalisation analyses were conducted to help pinpoint causal genes. We further constructed polygenic risk scores to explore options for personalized risk assessment and prevention. Main results and the role of chance In the discovery phase, we identified 18 genetic loci and 20 genetic variants significantly associated with POP (p &lt; 5 × 10−8) and 75% of the variants show nominal significance association (p &lt; 0.05) in the replication. Notably, the joint meta-analyses detected 20 genetic loci significantly associated with POP, from which 13 loci were novel. Novel genetic variants are located in or near genes involved in gestational duration and preterm birth (rs2687728 p = 2.19x10-9, EEFSEC), cardiovascular health and pregnancy success (rs1247943 p = 5.83x10-18, KLF13), endometriosis (rs12325192 p = 3.72x10-18, CRISPLD2), urogenital tract development (rs7126322, p = 4.35x10-15, WT1 and rs42400, p = 4.8x10-10, ADAMTS16) and regulation of the oxytocin receptor (rs2267372, p = 4.49x10-13, MAFF). Further analyses demonstrated that POP GWAS signals colocalise with several eQTLS (including EEFSEC, MAFF, KLF13, etc.), providing further evidence for mapping associated genes. Tissue and cell enrichment analyses underlined the role of the urogenital system, muscle cells, myocytes and adipocytes (p &lt; 0.00001, FDR&lt;0.05). Furthermore, genetic correlation analyses supported a shared genetic background with gastrointestinal disorders, joint and musculoskeletal disorders and cardiovascular disease. Polygenic risk scores analyses included a total of 125551 people in the target dataset, with 5379 prevalent patients and 2517 incident patients. Analyzing the best GRS as a quintile showed association with incident disease (Harrell c-statistic= 0.603, SD = 0.006). Limitations, reasons for caution This GWAS meta-analyses focused on European ancestry populations, which challenges the generalizability of GWAS findings to non-European populations. Moreover, this study included women with PP from population-based biobanks identified using the ICD-10 code N81, which limits analyses considering different disease stages and severity. Wider implications of the findings Our study provides genetic evidence to improve the current understanding of PP pathogenesis and serves as basis for further functional studies. Moreover, we provide a genetic tool for personalized risk stratification, which could help prevent PP development and improve the quality of a vast quantity of women. Trial registration number not applicable

scholarly journals Discovery of three loci increasing resistance to charcoal rot caused by Macrophomina phaseolina in octoploid strawberry

2021 ◽  
Vol 11 (3) ◽  
Author(s):  
Jonathan R Nelson ◽  
Sujeet Verma ◽  
Nahla V Bassil ◽  
Chad E Finn ◽  
James F Hancock ◽  
...  
Keyword(s):  
Linkage Group ◽  
Genetic Architecture ◽  
Production Systems ◽  
Macrophomina Phaseolina ◽  
Economic Problem ◽  
Phenotypic Variance ◽  
Charcoal Rot ◽  
Partial Dominance ◽  
Growing Seasons ◽  
Genome Wide

Abstract Charcoal rot caused by Macrophomina phaseolinais an increasing economic problem in annualized strawberry production systems around the world. Currently there are no effective postfumigation chemical controls for managing charcoal rot, and no information is available on the genetic architecture of resistance to M. phaseolina in strawberry (Fragaria ×ananassa). In this study, three multiparental discovery populations and two validation populations were inoculated at planting and evaluated for mortality in three consecutive growing seasons. Genome-wide SNP genotyping and pedigree-based analysis with FlexQTL™ software were performed. Two large-effect quantitative trait loci (QTL) increasing charcoal rot resistance were discovered and validated in cultivated germplasm. FaRMp1 was located on linkage group 2A in the interval 20.4to 24.9 cM, while FaRMp2 was located on linkage group 4B in the interval 41.1to 61.2 cM. Together these QTLs explained 27% and 17% of the phenotypic variance in two discovery populations consisting of elite breeding germplasm. For both QTLs, the resistant allele showed some evidence of partial dominance, but no significant interaction was detected between the two loci. As the dosage of resistant alleles increased from 0 to 4 across the two QTLs, mortality decreased regardless of the combination of alleles.A third locus, FaRMp3 on 4D, was discovered in FVC 11–58, a reconstituted F.×ananassa originating from diverse F. virginiana and F. chiloensis accessions. This locus accounted for 44% of phenotypic variation in four segregating crosses. These findings will form the basis for DNA-informed breeding for resistance to charcoal rot in cultivated strawberry.

scholarly journals Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations

2016 ◽  
Vol 25 (6) ◽  
pp. 1215-1224 ◽  
Author(s):  
Yao Hu ◽  
Huaixing Li ◽  
Ling Lu ◽  
Ani Manichaikul ◽  
Jingwen Zhu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Polyunsaturated Fatty Acid ◽  
European Ancestry ◽  
Genome Wide ◽  
Meta Analyses

scholarly journals Exome wide association study on Albuminuria identifies a novel rare variant inCUBNand additional genes, in 33985 Europeans with and without diabetes

2018 ◽  
Author(s):  
Tarunveer S. Ahluwalia ◽  
Christina-Alexendra Schulz ◽  
Johannes Waage ◽  
Tea Skaaby ◽  
Niina Sandholm ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Association Study ◽  
Genetic Architecture ◽  
European Ancestry ◽  
Common Variants ◽  
Multiple Testing Correction ◽  
Meta Analyses ◽  
Coding Variants ◽  
Prevention Of Diabetes

AbstractIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease (CKD) and end-stage renal disease which are highly prevalent in patients with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited with the majority of studies focusing on common variants.We performed an exome-wide association study to identify coding variants in a two phase (discovery and replication) approach, totaling to 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and further testing in Greenlanders (n = 2,605). We identify a rare (MAF: 0.8%) missense (A1690V) variant inCUBN(rs141640975, β=0.27, p=1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analyses. Presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rareCUBNvariant had 3 times stronger effect in individuals with diabetes compared to those without(pinteraction:5.4 × 10−4, βDM: 0.69, βnonDM:0.20) in the discovery meta-analyses. Geneaggregate tests based on rare and common variants identify three additional genes associated with albuminuria(HES1, CDC73, andGRM5)after multiple testing correction (P_bonferroni<2.7 × 10−6).The current study identifies a rare coding variant in theCUBNlocus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. These findings provide new insights into the genetic architecture of albuminuria and highlight novel target genes and pathways for prevention of diabetes-related kidney disease.Significance statementIncreased albuminuria is a key manifestation of major health burdens, including chronic kidney disease and/or cardiovascular disease. Although being partially heritable, there is a lack of knowledge on rare genetic variants that contribute to albuminuria. The current study describes the discovery and validation, of a new rare gene mutation (~1%) in theCUBNgene which associates with increased albuminuria. Its effect multiplies 3 folds among diabetes cases compared to non diabetic individuals. The study further uncovers 3 additional genes modulating albuminuria levels in humans. Thus the current study findings provide new insights into the genetic architecture of albuminuria and highlight novel genes/pathways for prevention of diabetes related kidney disease.

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