Multi-ethnic Genome-wide Association Studies Research Articles

Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P < 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.

#162 Single-nucleus RNA-seq of biopsy-confirmed IgA nephropathy reveals cell-specific transcriptomic alteration

Abstract Background and Aims Single-nucleus RNA-seq (SnRNA-seq) is a valuable method for identifying cell-specific transcriptomic alterations in kidney cells. Our objective was to investigate SnRNA-seq data from biopsy-confirmed IgA nephropathy (IgAN) cases and identify cell-specific alterations in the transcriptome. Method We collected snap-frozen kidney biopsy tissues from 6 cases of IgA nephropathy (IgAN) and 7 nephrectomy control cases. The disease control group included 3 cases of diabetic kidney disease, 6 cases of minimal change disease, and 6 PLA2R-Ab positive membranous nephropathy cases. SnRNA-seq was performed on the kidney tissues, and kidney cells were identified in the dataset through UMAP clustering. We investigated differences in the proportion of kidney cell types and identified differentially expressed genes (DEGs). Additionally, we searched for representative gene loci previously reported in a multiethnic genome-wide association study (GWAS). Results We successfully collected transcriptomic profiles of >50 000 cells from IgAN, with a considerable enrichment of intraglomerular cells. The DEG analysis revealed a high number of DEGs in mesangial cells, fibroblasts, and vascular smooth muscle cells in the IgAN transcriptome compared to the nephrectomy and disease control cases. In the gene set enrichment analysis, the epithelial-mesenchymal transition pathway was enriched in the glomerular cells of IgAN. Furthermore, among various GWAS loci, ETS1 was the gene significantly highly expressed in the mesangial cells of IgAN, consistent across the compared control groups. Conclusion This investigation represents the largest SnRNA-Seq profiling of IgAN kidney cells to date. We identified notable enriched cell-specific pathways in IgAN. ETS1 may be a kidney-indwelling causal factor for IgAN pathophysiology, considering its notable significance in both previous GWAS results and the current SnRNA-Seq data.

Abstract 6146: Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS

Abstract Prostate cancer (PCa) is a complex disease with the second leading cause of cancer death in US males. Multi-ethnic genome-wide association studies (GWAS) identified a thousand genetic variants associated with PCa risk in different races. However, the majority of risk variants are located in non-coding regions, making it challenging to understand their contribution to PCa risk. Non-coding regions include functional regulatory elements (REs) such as promoters and enhancers, whose activity can be evaluated by histone modification H3K4me3 and H3K27ac, respectively. In this study, we integrated PCa risk variants with hundreds of H3K4me3 and H3K27ac ChIP-seq data from normal and cancer prostate cell lines and tissues, finding 122 variants in promoters and 301 variants in enhancers. Enhancers are distal to promoters, and they form loops to regulate gene expression, mediated by transcription factors (TFs). Enhancer activities are tightly associated with cell fate. Genetic variants can affect the activity of enhancers by changing the binding preference of TFs and such changes can affect chromatin interactions and dysregulate gene expression. We hypothesize that allele changes of enhancer variants contribute to PCa risk differently among individuals from different ancestries, leading to the development of heterogeneous PCa molecular subgroups, characterized by genetic alterations including TMPRSS2-ERG fusion. By integrating H3K27ac ChIP-seq data from prostate cell lines derived from European (EUR) and African (AFR) ancestries, we found 185 risk variants in enhancers in EUR cell lines and 69 risk variants in enhancers in AFR cell lines. Next, we integrated patient tissue-derived H3K27ac ChIP-seq data and performed chromatin quantitative trait loci (cQTL) and allelic imbalance (AI) analyses to determine risk variants associated with enhancer activity. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 130 and 46 with significant association, respectively. To determine TFs that change binding upon allele change of enhancer risk variants, we integrated hundreds of TF ChIP-seq data from prostate cell lines and tissues. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 142 and 44 variants bound by TFs, respectively. When we further performed cQTL and AI analyses for FOXA1, HOXB13, and AR, we found 87 and 29 variants significantly associated with TF binding affinity, respectively. Moreover, we found that these associations differ between TMPRSS2-ERG fusion positive and negative tumors. To identify the target genes of enhancer risk variants, we are currently integrating chromatin interaction data including Hi-C and Micro-C. Overall, this study provides valuable insights into the underlying molecular mechanisms of risk variants in various populations and individuals which lead to the development of heterogeneous PCa subgroups. Citation Format: Zexun Wu, Andrew Vu, Ethan S. Nelson-Moore, Huan Cao, Suhn K. Rhie. Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6146.

Causal associations of refractive error and early age-related macular degeneration: A Mendelian randomization study

This study aims to determine the risk associated with early age-related macular degeneration (AMD) due to refractive errors (RE) using an analysis of genome-wide association study (GWAS) data through the two-sample Mendelian randomization approach. Single-nucleotide polymorphisms (SNPs) linked to refractive errors (RE) were obtained from numerous GWAS studies involving individuals of European descent. The data for early AMD was obtained from a diverse, multiethnic GWAS meta-analysis that included 105,248 participants (14,034 cases and 91,214 controls). The primary outcome measure focused on the rise in early AMD risk corresponding to a 1-diopter alteration in spherical power and cylindrical power. In the main Mendelian randomization analysis, inverse-variance weighting (IVW) methods were applied for the evaluation. Mendelian Randomization (MR) study revealed a substantial impact of refractive error (RE) on early AMD risk, with a 1-diopter increase in hypermetropia being related to a 1.16 odds ratio (OR) for a greater risk of early AMD (95% CI, 1.10–1.23; P < 0.01). This conclusion was further supported by four supplementary approaches, namely, Weighted mode, Weighted-median, Simple mode, and MR-Egger. The results suggest a heightened risk of early AMD correlated with hyperopia, necessitating further research to thoroughly elucidate this potential causal relationship.

Multi-Ethnic Genome-Wide Association Study (GWAS) for Idiopathic Nephrotic Syndrome Identifies Susceptibility Loci Across the Life Span, Response to Therapy, and Genetic Ancestry

Multi-Ethnic Genome-Wide Association Study (GWAS) for Idiopathic Nephrotic Syndrome Identifies Susceptibility Loci Across the Life Span, Response to Therapy, and Genetic Ancestry

Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.

Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking. The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P<5×10-8. Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P=2.42×10-6; African ancestry: HR, 1.51; P=4.43×10-3; HR in meta-analysis, 1.41; P=4.25×10-8). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P<0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment (P>0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P=1.59×10-5). In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. URL: https://www. gov; Unique identifier: NCT00475852.

Multivariate adaptive shrinkage improves cross-population transcriptome prediction and association studies in underrepresented populations

Transcriptome prediction models built with data from European-descent individuals are less accurate when applied to different populations because of differences in linkage disequilibrium patterns and allele frequencies. We hypothesized that methods that leverage shared regulatory effects across different conditions, in this case, across different populations, may improve cross-population transcriptome prediction. To test this hypothesis, we made transcriptome prediction models for use in transcriptome-wide association studies (TWASs) using different methods (elastic net, joint-tissue imputation [JTI], matrix expression quantitative trait loci [Matrix eQTL], multivariate adaptive shrinkage in R [MASHR], and transcriptome-integrated genetic association resource [TIGAR]) and tested their out-of-sample transcriptome prediction accuracy in population-matched and cross-population scenarios. Additionally, to evaluate model applicability in TWASs, we integrated publicly available multiethnic genome-wide association study (GWAS) summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study and Pan-ancestry genetic analysis of the UK Biobank (PanUKBB) with our developed transcriptome prediction models. In regard to transcriptome prediction accuracy, MASHR models performed better or the same as other methods in both population-matched and cross-population transcriptome predictions. Furthermore, in multiethnic TWASs, MASHR models yielded more discoveries that replicate in both PAGE and PanUKBB across all methods analyzed, including loci previously mapped in GWASs and loci previously not found in GWASs. Overall, our study demonstrates the importance of using methods that benefit from different populations' effect size estimates in order to improve TWASs for multiethnic or underrepresented populations.

A multiethnic genome-wide analysis of 19,420 individuals identifies novel loci associated with axial length and shared genetic influences with refractive error and myopia.

Introduction: Long axial length (AL) is a risk factor for myopia. Although family studies indicate that AL has an important genetic component with heritability estimates up to 0.94, there have been few reports of AL-associated loci. Methods: Here, we conducted a multiethnic genome-wide association study (GWAS) of AL in 19,420 adults of European, Latino, Asian, and African ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, with replication in a subset of the Consortium for Refractive Error and Myopia (CREAM) cohorts of European or Asian ancestry. We further examined the effect of the identified loci on the mean spherical equivalent (MSE) within the GERA cohort. We also performed genome-wide genetic correlation analyses to quantify the genetic overlap between AL and MSE or myopia risk in the GERA European ancestry sample. Results: Our multiethnic GWA analysis of AL identified a total of 16 genomic loci, of which 5 are novel. We found that all AL-associated loci were significantly associated with MSE after Bonferroni correction. We also found that AL was genetically correlated with MSE (rg = -0.83; SE, 0.04; p = 1.95 × 10-89) and myopia (rg = 0.80; SE, 0.05; p = 2.84 × 10-55). Finally, we estimated the array heritability for AL in the GERA European ancestry sample using LD score regression, and found an overall heritability estimate of 0.37 (s.e. = 0.04). Discussion: In this large and multiethnic study, we identified novel loci, associated with AL at a genome-wide significance level, increasing substantially our understanding of the etiology of AL variation. Our results also demonstrate an association between AL-associated loci and MSE and a shared genetic basis between AL and myopia risk.

Analysis of GPR126 polymorphisms and their relationship with scoliosis in Marfan syndrome and Marfan-like syndrome in Mexican patients.

Marfan syndrome (MFS) is an inherited connective tissue disorder. As the spinal growth depends on delicate balance of forces, conditions that affect musculoskeletal matrix often lead to spinal deformities. A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS. Multi-ethnic genome-wide association studies and analyses of human genetic mutations showed that variations and mutations of G protein-coupled receptor 126 (GPR126)locus are associated with multiple skeletal defects, including shorter stature and adolescent idiopathic scoliosis. The study included 54 patients with MFS and 196 control patients. The DNA was extracted from peripheral blood using the saline expulsion method and single nucleotide polymorphism (SNP) determination was carried out using TaqMan probes. Allelic discrimination was performed by RT-qPCR. Significant differences in genotype frequencies were found for SNP rs6570507 in relation to MFS and sex (recessive model, OR 2.46, 95% CI 1.03 -5.87; P = 0.03) and rs7755109 (overdominant model, OR 0.39, 95% CI 0.16-0.91; P = 0.03). The most significant association was found in SNP rs7755109, where the frequency of genotype AG was significantly different between MFS patients with scoliosis and those without (OR 5.68, 95% CI 1.09-29.48; P=0.04). This study, for the first time, examined the genetic association of SNP GPR126 with the risk of scoliosis in patients with connective tissue diseases. The study revealed that SNP rs7755109 is associated with the presence of scoliosis in Mexican patients with MFS.

Serum 25-Hydroxyvitamin D Levels and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study.

Observational studies have linked vitamin D insufficiency to pediatric type 2 diabetes (T2D), but evidence from vitamin D supplementation trials is sparse. Given the rising prevalence of pediatric T2D in all ethnicities, determining the protective role of vitamin D has significant public health importance. We tested whether serum 25-hydroxyvitamin D (25OHD) levels are causally linked to youth-onset T2D risk using Mendelian randomization (MR). We selected 54 single-nucleotide polymorphisms (SNPs) associated with 25OHD in a European genome-wide association study (GWAS) on 443,734 individuals and obtained their effects on pediatric T2D from the multi-ethnic PRODIGY GWAS (3006 cases/6061 controls). We applied inverse variance weighted (IVW) MR and a series of MR methods to control for pleiotropy. We undertook sensitivity analyses in ethnic sub-cohorts of PRODIGY, using SNPs in core vitamin D genes or ancestry-informed 25OHD SNPs. Multivariable MR accounted for the mediating effects of body mass index. We found that a standard deviation increase in 25OHD in the logarithmic scale did not affect youth-onset T2D risk (IVW MR odds ratio (OR) = 1.04, 95% CI = 0.96-1.13, p = 0.35) in the multi-ethnic analysis, and sensitivity, ancestry-specific and multivariable MR analyses showed consistent results. Our study had limited power to detect small/moderate effects of 25OHD (OR of pediatric T2D < 1.39 to 2.1). In conclusion, 25OHD levels are unlikely to have significant effects on the risk of youth-onset T2D across different ethnicities.

P1481: THE INTERNATIONAL HEMOGLOBINOPATHY RESEARCH NETWORK (INHERENT): AN INTERNATIONAL INITIATIVE TO STUDY THE ROLE OF GENETIC MODIFIERS IN HEMOGLOBINOPATHIES

Background: Haemoglobinopathies, including sickle cell disease (SCD) and thalassaemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenicity is well established, the diverse clinical manifestations and the varying degree of severity are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterisation of a few genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalised treatment. There is a growing need for deeper insight with the availability of novel targeted therapies and potentially curative options like gene therapy in both SCD and thalaessemia. Aims: The International Haemoglobinopathy Research Network (INHERENT) is a recently established network with the aim of investigating the role of genetic modifiers in haemoglobinopathies, through a large-scale, multi-ethnic genome-wide association study (GWAS). Methods: INHERENT brings together nine existing international or regional consortia in the field of haemoglobinopathies, namely ITHANET, RADeep, ARISE, SPARCO, SADaCC, REDAC, the HVP Global Globin Network, the International Health Repository, and the ClinGen Haemoglobinopathy VCEP. The activities of INHERENT are currently divided into five working groups, as follows: clinical, genotyping, data management and analysis, ethics, and knowledge translation. Participation in INHERENT is open for any group that can submit a minimum number of samples with their core phenotypic description. INHERENT membership is international and interdisciplinary and, currently, includes over 160 experts from 89 organisations, spanning 36 countries worldwide. INHERENT aims to recruit over 30,000 hemoglobinopathy patients, which is larger than any previous GWAS in the field. Results: A survey amongst 67 (80%) of the participating centers revealed that INHERENT has the potential to recruit over 73 500 patients, of which 53 755 are SCD, 15 691 are β thalassemia (62% transfusion dependent), 4 179 (α thalassemia). A sample size of 10 000 individuals can detect associations down to MAF=0.05 with an OR=1.5 in binary phenotypes assuming a case/control ratio of 0.3 and p value 5x108. For survival endpoints, 5000 individuals will be sufficient to detect a HR=1.5 and MAF 0.05 if we assume an event rate of 30%. Summary/Conclusion: We demonstrate that the current membership of INHERENT has the potential to reach this sample size target. The large increase in the sample size and the diversity in the studied populations will enable novel discoveries and expand knowledge on haemoglobinopathy genetics, thus paving the way for advancing the science of personalised diagnosis and treatment.

Abstract TP137: Ethnic/racial Variations Of Intracerebral Hemorrhage Genetics (erich-gene) Study Protocol

Introduction: Epidemiologic studies of intracerebral hemorrhage (ICH) have consistently demonstrated variation in incidence, location, comorbidity burden, age-of-onset, and outcome by race and ethnicity, and genetic studies have identified differences in risk mediated by genetic risk factors such as Apolipoprotein E (APOE). We report the design and methods of the largest multi-ethnic genome-wide association study (GWAS) of ICH risk and outcome conducted to date. Methods: The Ethnic/Racial Variations of ICH Genetics (ERICH-GENE) study is an international, multi-center, genetic case-control study of ICH. Cases are individuals with confirmed primary ICH with biosample availability and consent compatible with shareable genome-wide genotyping or previous genotyping. Central neuroimaging phenotype harmonization of case status, hemorrhage location, and imaging characteristics of cerebral small vessel disease including leukoaraiosis, atrophy, microbleeds, intraventricular hemorrhage severity and volume of ICH measurements will be performed. Controls are ICH-free individuals of compatible age and race/ethnicity from existing studies and biorepositories. Results: As of August 2021, 2,002 ICH cases have been collected and genotyped, in addition to 2,558 already-genotyped ICH cases from the multi-ethnic ERICH study. 5,600 total new ICH cases will be genotyped under ERICH-GENE, with planned meta-analyses across existing ICH GWAS datasets and international biobanks totaling &gt;20,000 cases. We are on schedule to meet our genotyping goal within the study period. Non-European ancestry cases are being prioritized for genotyping and ~66% of the previously genotyped ERICH cases are black or Hispanic. From available cases, a total of 10,621 neuroimaging studies have been uploaded for central adjudication to date with 6,278 having undergone harmonization. Conclusions: ERICH-GENE is a large, multi-ethnic, international, centrally harmonized GWAS of ICH risk and outcome that will identify genetic risk factors across diverse populations for biological discovery and population-specific risk stratification.

Ancestry- and sex-specific effects underlying inguinal hernia susceptibility identified in a multiethnic genome-wide association study meta-analysis

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however, it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5 × 10−8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

P117: THE INTERNATIONAL HAEMOGLOBINOPATHY RESEARCH NETWORK (INHERENT): AN INTERNATIONAL INITIATIVE TO STUDY THE ROLE OF GENETIC MODIFIERS IN HAEMOGLOBINOPATHIES

Background: Haemoglobinopathies, including sickle cell disease (SCD) and thalassaemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenicity is well established, the diverse clinical manifestations and the varying degree of severity are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterisation of a few genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalised treatment. There is a growing need for deeper insight with the availability of novel targeted therapies and potentially curative options like gene therapy in both SCD and thalaessemia. Aims: The International Haemoglobinopathy Research Network (INHERENT) is a recently established network with the aim of investigating the role of genetic modifiers in haemoglobinopathies, through a large-scale, multi-ethnic genome-wide association study (GWAS). Methods: INHERENT brings together nine existing international or regional consortia in the field of haemoglobinopathies, namely ITHANET, RADeep, ARISE, SPARCO, SADaCC, REDAC, the HVP Global Globin Network, the International Health Repository, and the ClinGen Haemoglobinopathy VCEP. The activities of INHERENT are currently divided into five working groups, as follows: clinical, genotyping, data management and analysis, ethics, and knowledge translation. Participation in INHERENT is open for any group that can submit a minimum number of samples with their core phenotypic description. INHERENT membership is international and interdisciplinary and, currently, includes over 160 experts from 89 organisations, spanning 36 countries worldwide (Figure). INHERENT aims to recruit over 30,000 haemoglobinopathy patients, which is over one order of magnitude larger than any previous GWAS in the field. Summary: We demonstrate that the current membership of INHERENT has the potential to reach this sample size target. The large increase in the sample size and the diversity in the studied populations will enable novel discoveries and expand knowledge on haemoglobinopathy genetics, thus paving the way for advancing the science of personalised diagnosis and treatment.

Genome-wide association study-based prediction of atrial fibrillation using artificial intelligence

ObjectiveWe previously reported early-onset atrial fibrillation (AF) associated genetic loci among a Korean population. We explored whether the AF-associated single-nucleotide polymorphisms (SNPs) selected from the Genome-Wide Association Study (GWAS) of...

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study.

Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. Four novel associations were identified (p < 5 × 10-9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ).

The International Hemoglobinopathy Research Network (INHERENT): An International Initiative to Study the Role of Genetic Modifiers in Hemoglobinopathies

Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenicity is well established, the diverse clinical manifestations and the varying degree of severity are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterization of a few genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalized treatment. There is a growing need for deeper insight with the availability of novel targeted therapies and potentially curative options like gene therapy in both SCD and thalassemia.The International Hemoglobinopathy Research Network (INHERENT) is a recently established network with the aim of investigating the role of genetic modifiers in hemoglobinopathies, through a large-scale, multi-ethnic genome-wide association study (GWAS). INHERENT brings together nine existing international or regional consortia in the field of hemoglobinopathies, namely ITHANET, RADeep, ARISE, SPARCO, SADaCC, REDAC, the HVP Global Globin Network, the International Health Repository, and the ClinGen Hemoglobinopathy VCEP. The activities of INHERENT are currently divided into five working groups, as follows: clinical, genotyping, data management and analysis, ethics, and knowledge translation. Participation in INHERENT is open for any group that can submit a minimum number of samples with their core phenotypic description. INHERENT membership is international and interdisciplinary and, currently, includes over 160 experts from 89 organizations, spanning 36 countries worldwide (Figure).INHERENT aims to recruit over 30,000 hemoglobinopathy patients, which is over one order of magnitude larger than any previous GWAS in the field. We demonstrate that the current membership of INHERENT has the potential to reach this sample size target. The large increase in the sample size and the diversity in the studied populations will enable novel discoveries and expand knowledge on hemoglobinopathy genetics, thus paving the way for advancing the science of personalized diagnosis and treatment. [Display omitted] DisclosuresArcher: Haemonetics: Current equity holder in publicly-traded company. Kuo: Bluebird Bio: Consultancy; Celgene: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Mañú Pereira: Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Multiethnic genome-wide and HLA association study of total serum IgE level

Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N= 21,901). We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. We identified 6 loci at genome-wide significance (P< 5×10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery= 2×10-4; Preplication= 5×10-4; Pdiscovery+replication= 4×10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication= 8×10-8). We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios.

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts– the most common craniofacial birth defects in humans– are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10−8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10−6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.

Abstract NG03: Multiethnic prostate cancer GWAS meta-analysis identifies novel variants, improves genetic risk prediction across populations, and informs biological mechanisms of prostate cancer

Abstract Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. The inadequate representation of diverse populations in current genome-wide association studies (GWAS) limits the translational potential of findings to the world's populations and could result in biased risk prediction, further exacerbating health disparities. To improve our understanding of genetic risk of PCa, we conducted the largest multiethnic PCa GWAS meta-analysis to date with 107,247 cases and 127,006 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8,611 cases and 18,809 controls of Asian ancestry, and 2,714 cases and 5,239 controls of Hispanic ethnicity. We identified 269 genetic risk variants independently associated with PCa risk, 86 of which were novel. Of the 183 previously reported prostate cancer risk variants, we identified stronger markers of risk for 62 variants using fine-mapping. To understand the aggregate effect of the 269 variants, we constructed a genetic risk score (GRS) using the multiethnic weights of the risk variants. Compared to men in the average 40-60% GRS category, the estimated OR for men in the top GRS decile (90-100%) was 5.06 [95% CI 4.84-5.29] for men of European ancestry, 3.74 [95% CI 3.36-4.17] for men of African ancestry, 4.47 [95% CI 3.52-5.68] for men of Asian ancestry, and 4.15 [95% CI 3.33-5.17] for Hispanic men. Men of African ancestry were estimated to have a 2.18-times higher mean GRS [95% CI 2.14-2.22], and men of Asian ancestry 0.73-times lower [95% CI 0.71-0.76], than men of European ancestry. Age significantly modified the GRS association with PCa risk, such that in men of European ancestry, the top decile GRS category was associated with an OR of 6.71 [95 % CI 5.99-7.52] for men ages 55 years or younger and 4.39 [95% CI 4.19-4.60] for men older than 55 years. Similarly, in men of African ancestry, the top GRS decile category was associated with an OR of 4.70 [95 % CI 3.65-6.07] for men ages 55 years or younger and 3.37 [95% CI 2.99-3.80] for men older than 55 years. We found that 51% of aggressive cases of European ancestry and 45% of aggressive cases of African ancestry were within the top 20% of the GRS. The lifetime absolute risk of PCa for men in the top decile of the GRS reached 38% for both African Americans [95% CI 36-41%] and Whites [95% CI 37-39%], 31% [95% CI 27-36%] for Hispanics and 26% [95% CI 22-30%] for Asians. For comparison, we constructed a genome-wide GRS, including the 269 variants and variants associated with PCa with P&amp;lt;1.0 × 10−5. ORs calculated with genome-wide GRS were similar and had nearly identical discriminative ability as the 269 GRS in independent samples of 6,852 cases and 193,117 controls of European ancestry and 1,586 cases and 1,047 controls of African ancestry. This suggests that a genome-wide GRS may not have improved ability to predict PCa risk compared to the 269 GRS. To understand the biological mechanisms impacted by genetic risk of PCa, we conducted integrative analyses of the GRS and serum metabolomics in 611 African ancestry men from the Multiethnic Cohort. We found that a higher GRS was associated with lower sphingolipid levels (beta=-0.08, P=3.1 × 10−4), lower androgenic steroids (beta=-0.06, P=0.003), and higher sarcosine levels (beta=0.11, P=0.002). Further, using a latent clustering approach, we found that these metabolites in conjunction with the GRS contributed to the clustering of men with low-risk, intermediate-risk, and high-risk of PCa. These findings support the role of germline variation contributing to racial and ethnic disparities in PCa risk, with the GRS offering an approach for personalized risk prediction across populations and informing the biological mechanisms underlying PCa risk. Citation Format: Burcu F. Darst, Lilit Moss, Edward J. Saunders, Nicholas Mancuso, Xin Sheng, Alisha Chou, Tokhir Dadaev, Sonja I. Berndt, Stephen K. Van Den Eeden, Stephen J. Chanock, Michael B. Cook, Tracy M. Layne, Demetrius Albanes, Hidewaki Nakagawa, John S. Witte, Practical Consortium, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multiethnic prostate cancer GWAS meta-analysis identifies novel variants, improves genetic risk prediction across populations, and informs biological mechanisms of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG03.