Asian Ancestry Research Articles

Evaluating the frequency and the impact of pharmacogenetic alleles in an ancestrally diverse Biobank population

BackgroundPharmacogenomics (PGx) aims to utilize a patient’s genetic data to enable safer and more effective prescribing of medications. The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides guidelines with strong evidence for 24 genes that affect 72 medications. Despite strong evidence linking PGx alleles to drug response, there is a large gap in the implementation and return of actionable pharmacogenetic findings to patients in standard clinical practice. In this study, we evaluated opportunities for genetically guided medication prescribing in a diverse health system and determined the frequencies of actionable PGx alleles in an ancestrally diverse biobank population.MethodsA retrospective analysis of the Penn Medicine electronic health records (EHRs), which includes ~ 3.3 million patients between 2012 and 2020, provides a snapshot of the trends in prescriptions for drugs with genotype-based prescribing guidelines (‘CPIC level A or B’) in the Penn Medicine health system. The Penn Medicine BioBank (PMBB) consists of a diverse group of 43,359 participants whose EHRs are linked to genome-wide SNP array and whole exome sequencing (WES) data. We used the Pharmacogenomics Clinical Annotation Tool (PharmCAT), to annotate PGx alleles from PMBB variant call format (VCF) files and identify samples with actionable PGx alleles.ResultsWe identified ~ 316.000 unique patients that were prescribed at least 2 drugs with CPIC Level A or B guidelines. Genetic analysis in PMBB identified that 98.9% of participants carry one or more PGx actionable alleles where treatment modification would be recommended. After linking the genetic data with prescription data from the EHR, 14.2% of participants (n = 6157) were prescribed medications that could be impacted by their genotype (as indicated by their PharmCAT report). For example, 856 participants received clopidogrel who carried CYP2C19 reduced function alleles, placing them at increased risk for major adverse cardiovascular events. When we stratified by genetic ancestry, we found disparities in PGx allele frequencies and clinical burden. Clopidogrel users of Asian ancestry in PMBB had significantly higher rates of CYP2C19 actionable alleles than European ancestry users of clopidrogrel (p < 0.0001, OR = 3.68).ConclusionsClinically actionable PGx alleles are highly prevalent in our health system and many patients were prescribed medications that could be affected by PGx alleles. These results illustrate the potential utility of preemptive genotyping for tailoring of medications and implementation of PGx into routine clinical care.

Obesity Pillars Roundtable: Body mass index and body composition in Black and Female individuals. Race-relevant or racist? Sex-relevant or sexist?

BackgroundBody mass index (BMI or weight in kilograms/height in meters2) is the most common metric to diagnose overweight and obesity. However, a body composition analysis more thoroughly assesses adiposity, percent body fat, lean body mass (i.e., including skeletal muscle), and sometimes bone mineral density. BMI is not an accurate assessment of body fat in individuals with increased or decreased muscle mass; the diagnostic utility of BMI in individuals is also influenced by race and sex. MethodsPrevious Obesity Pillars Roundtables addressed the diagnostic limitations of BMI, the importance of android and visceral fat (especially among those with South and East Asian ancestry), and considerations of obesity among individuals who identify as Hispanic, diverse in sexual-orientation, Black, Native American, and having ancestry from the Mediterranean and Middle East regions. This roundtable examines considerations of BMI in Black and female individuals. ResultsThe panelists agreed that body composition assessment was a more accurate measure of adiposity and muscle mass than BMI. When it came to matters of race and sex, one panelist felt: “race is a social construct and not a defining biology.” Another felt that: “BMI should be a screening tool to prompt further evaluation of adiposity that utilizes better diagnostic tools for body composition.” Regarding bias and misperceptions of resistance training in female individuals, another panelist stated: “I have spent my entire medical career taking care of women and have never seen a woman unintentionally gain ‘too much’ muscle mass and bulk up from moderate strength training.” ConclusionsConveying the importance of race and sex regarding body composition has proven challenging, with the discussion sometimes devolving into misunderstandings or misinformation that may be perceived as racist or sexist. Body composition analysis is the ultimate diagnostic equalizer in addressing the inaccuracies and biases inherent in the exclusive use of BMI.

Variability in Pattern of Mutational Signatures in Multiple Myeloma As a Function of Racial Origin

Introduction: Current data suggests Black/African Americans (AA) have an increased risk of developing multiple myeloma (MM), especially in comparison to White/European Americans (EA). However, the underlying causes remain unclear. Genetic definition of the spectrum of acquired mutations and the signatures they contain could help us to understand the mechanism underlying this excess risk. Currently, only limited information is available on the mutational spectra within AAs and the majority of data that has been generated is based on the societal construct of self-identified race/ethnicity alone. To address this deficiency and the potential associated bias, it is critical to examine greater numbers of whole genome sequencing (WGS) data from AAs. Data from a pilot study indicate a prolonged and more intense exposure to the germinal center (GC) reaction in the early evolutionary phases of MM within AAs, suggesting that it is essential to examine sequencing data from early disease stage i.e. smoldering MM (SMM) to better understand genetic predisposition in AAs. Methods: To address the mutational basis of MM and how it varies based on racial origin we carried out two large studies, Polyethnic-1000 and the Smoldering Myeloma Registration Trial (SMRT) study. Furthermore, we examined a cross-sectional series of WGS and whole exome sequencing (WES) data derived from cases with SMM and MM already sequenced to characterize the pattern of mutations and the signatures in both the coding and non-coding regions of the genome. Importantly, to accurately infer racial ancestry, we built an admixture workflow into our sequencing analysis pipeline, enabling us to address the variability in origin from within the MM cases ranging from regions of Europe to subsets of cases with African, North/South American, and Asian origin directly. We showed its use in previous work describing the heterogenous genetic admixture in MM cases that self-identified Hispanic and Latino. Our pipeline uses a suite of well-supported bioinformatic tools for preprocessing sequencing data according to best practices, cataloguing germline variants across a large series of patients, generating ancestry admixture estimations per patient, determining telomere length and composition, and identifying the spectrum of somatic events including single nucleotide variants, small insertions/deletions, copy number variants, and structural variants using consensus calling. All source code and reference data is publicly available via a GitHub repository (https://github.com/pblaney/mgp1000). Results: We generated new WGS data from 65 MM cases (EA n=15, AA n=50), and 44 SMM cases (EA n=36, AA n=18) as part of the Polyethnic 1000 and SMRT study. We also systematically reanalyzed 473 cases with deep (>30x) WGS data and all cases in the CoMMpass study low-depth (5-12x) WGS (n=943). Estimating ancestral composition directly from the genetic data of the CoMMpass study, we identified discrepancies between the self-reported race and the genetically determined admixture composition. Approximately 75% of individuals identified as 'White' but 7% of these cases had a genetic composition that included greater than 10% contribution from African, North/South American, or Asian ancestry. More interesting, 18% identified as 'Black/African American' but 50% of these cases had greater than 10% contribution from European, North/South American, or Asian ancestry. These results demonstrate the underlying genetic heterogeneity in a population that is currently clinically classified as the homogenous and thus lead to skewed evaluations of race and outcome in MM. We will compare the mutational spectra within these groups with different origins to address the risk of developing MM as well as addressing the time of origin of MM within the different populations. Conclusion: We show that there is significant variability of admixture from Europe, North/South America, and Africa within patients who self-identify as White, Black/African American, or Hispanic/Latino in clinical datasets from the U.S. This reinforces the need for complementary genetic admixture with racial self-identification when investigating the links between racial ancestry and outcomes in MM. Figure: Admixture composition of CoMMpass study shows significant contribution of African, North/South American, and East/South Asian origins in predominant European ancestral background. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric Age at Hematopoietic Stem Cell Transplant: Associations with Non-Malignant Genetic Disease and Race

Introduction: Increasingly, hematopoietic stem cell transplant (HSCT) is used in pediatrics to treat both malignant and nonmalignant conditions. Many of the nonmalignant disorders for which HSCT is curative are genetic, and it has long been recognized that the diagnostic odyssey for patients with genetic disorders is frequently quite long. Notably, the diagnostic odyssey is longer for non-white patients with genetic diseases than for white patients with genetic diseases. We hypothesized that this disparity would also manifest as older age at time of HSCT, which could be associated with greater co-morbidities and worse outcomes. While previous studies have analyzed the association between race and pediatric HSCT access and survival, (PMID:32497418; 35071585; 34900869)we sought to determine if the diagnostic odyssey is longer for racial minorities compared to Caucasians. Methods: To test this hypothesis, we utilized the 2019 version of the Kids’ Inpatient Database (KID), developed by the Healthcare Cost and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality (AHRQ). The HSCT sample was identified using ICD-10-PCS Procedure Codes for transfusion of hematopoietic/cord blood stem cells: Allogenic: 30243X3, 30243Y3, 30243X4, 30233X4, 30243Y2; Autologous: 30243Y0. A variable for pediatric genetic disease (PGD) was generated using 348 ICD-10-CM diagnostic codes corresponding to 283 pediatric genetic diseases for which the carrier frequency is greater than 1 in 500 in the general population or in an at-risk subpopulation (e.g., sickle cell anemia in AA). We controlled for malignant disease leading to HSCT using ICD-10-CM diagnostic codes to identify lymphomas, leukemias, myelodysplastic syndrome, myeloproliferative neoplasms, neuroblastomas, and brain tumors. Multiple linear regression was used to test if age of HSCT procedure was significantly associated with race, known non-malignant PGD, malignant disease, payer status, and location (rural vs. urban). Results: We identified 1,178 pediatric aged patients (age 20 and younger) who received HSCT in 2019 (Allogenic N=618; autologous N=560). The clinical characteristics of these patients are described in Table 1. The average age for Caucasian pediatric patients treated with HSCT is 6.8 years (82 months). Comparing PGD vs. all other diagnoses related to HSCT, patients with known PGD are transplanted on average 1.9 years (22 months) earlier than matched controls (P<0.001). This difference persists after controlling for race, disease severity, transplant type, Medicaid status, and rural health system location. African American and Asian pediatric patients are treated with HSCT on average 1.6 years (18 months) older than matched Caucasian controls (P=0.003 and 0.032, respectively). The effect of race persists even after controlling for thalassemias and sickle cell disease, associated with non-European ancestry. Conclusions: Age at transplant may be a useful surrogate for ongoing health disparities and to inform real-world research. African American and Asian ancestries are associated with HSCT at an older age, suggesting a prolonged diagnostic or therapeutic odyssey. This effect persists after controlling for factors such as non-malignant and malignant conditions, payer status, rural location, and genetic diseases that are over-represented in racial groups. More work is required to determine if this delay in treatment is due to differences in the spectrum of genetic diseases treated by HSCT in children of different ancestries, and if these delays in therapy may be associated with increased comorbidities and worse HSCT outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Influence of Genetic Ancestry on Disease Biology in Pediatric T-Cell Acute Lymphoblastic Leukemia

Introduction: Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) is a biologically heterogenous disease that can be grouped into 16 subtypes based on integration of gene expression and somatic genomic alterations that have variable prevalence of activated targetable pathways (Pölönen P., et al ASH 2022). In both adult cancers and pediatric B-cell ALL, genetic ancestry has been associated with tumor biology and clinical outcomes; however, there is a paucity of data exploring the influence of genetic ancestry in T-ALL. Thus, we sought to determine the association of genetic ancestry with tumor biology in pediatric T-ALL. Methods: Whole genome sequencing (germline and tumor) and bulk RNA-sequencing was performed to characterize T-ALL subtype and pathway aberrations among 1312 newly diagnosed T-ALL patients treated on Children's Oncology Group trial AALL0434. Genetic ancestral composition was determined for each individual using the iAdmix program comparing allele frequencies between patients and reference genomes from the 1000 Genomes Project. Coefficients from the 5 reference populations (European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and American Admixture (AA)) were assumed to sum to 100%. Categorical genetic ancestral groups were classified from prior methods: "European" (EUR >90%), "African" (AFR >70%), "East Asian" (EAS >90%), "South Asian" (SAS >70%), and "Amerindian" (AA >10% and AA greater than AFR), with the rest defined as "Other." We evaluated associations of genetic ancestry with T-ALL molecular subtypes and pathways. Ancestry was first examined as a categorical variable using Fisher's exact test for its association with subtypes and pathways. Ancestry was also analyzed as a continuous variable using logistic regression for association with pathways and multinomial regression for association with subtype (TAL1-RB subtype as reference). The effect of ancestry was summarized as odds ratios (OR) for every 25% increase in a non-European ancestry, with a concurrent 25% decrease in European ancestry and remaining ancestries fixed. Results: Categorical ancestral composition in this cohort was 59% European, 11% African, 15% Amerindian, 3% East Asian, 2% South Asian, 10% Other. The prevalence of T-ALL subtypes differed by genetic ancestry (Figure 1). For example, HOXA9 and BCL11B, which are linked to ETP T-ALL, were significantly enriched in children of African genetic ancestry as compared to European ancestry (HOXA9: 11% AFR vs. 6% EUR; BCL11B: 3% AFR vs. 1.5% EUR). ETP phenotype was also more common in children of African descent as compared with European (11.9% vs. 7.5%, p =0.031). In analyses of ancestry as a continuous variable (with European as the reference), four subtypes and four pathways exhibited differences in odds of expression (Table 1). For every 25% increase in African ancestry, the odds of BCL11B subtype was 41% higher (p=0.034), odds of HOXA9 subtype was 26% higher (p=0.020), odds of MLLT10_TRA was 68% higher (p<0.001), and odds of tumor microenvironment (TME) aberrant subtype was 33% higher (p=0.027). For every 25% increase in African ancestry, patients were also 1.13-fold more likely to harbor JAK/STAT mutations (p=0.049) and 1.18-fold for MAPK/RAS pathway alterations (p=0.011), with decreasing odds of NOTCH mutations (OR=0.88, p=0.014) or ribosomal gene alterations (OR=0.69, p=0.003). For increasing East Asian ancestry, patients were also less likely to have NOTCH pathway alteration (OR=0.85, p=0.027), whereas there was no difference for increasing South Asian ancestry. Conclusion: Disease biology varies substantially among children of different genetic ancestries with T-ALL. Given that subtypes may inform future risk stratification, and pathways may guide novel treatment strategies, examining subtype and pathway expression for children of all ancestral backgrounds is critical. Important biological indicators of risk may be missed when studying patients of a single genetic ancestral group or when focusing on averages for the entire cohort without taking into consideration variation in genetic ancestry. Analyses of survival by genetic ancestry within genomic groups are ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p<5.0×10-8 and a Bonferroni-corrected p<4.6×10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Analysis of clinically relevant variants from ancestrally diverse Asian genomes

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

Epidemiological characteristics and genetic alterations in adult diffuse glioma in East Asian populations.

Understanding the racial specificities of diseases-such as adult diffuse glioma, the most common primary malignant tumor of the central nervous system-is a critical step toward precision medicine. Here, we comprehensively review studies of gliomas in East Asian populations and other ancestry groups to clarify the racial differences in terms of epidemiology and genomic characteristics. Overall, we observed a lower glioma incidence in East Asians than in Whites; notably, patients with glioblastoma had significantly younger ages of onset and longer overall survival than the Whites. Multiple genome-wide association studies of various cohorts have revealed single nucleotide polymorphisms associated with overall and subtype-specific glioma susceptibility. Notably, only 3 risk loci-5p15.33, 11q23.3, and 20q13.33-were shared between patients with East Asian and White ancestry, whereas other loci predominated only in particular populations. For instance, risk loci 12p11.23, 15q15-21.1, and 19p13.12 were reported in East Asians, whereas risk loci 8q24.21, 1p31.3, and 1q32.1 were reported in studies in White patients. Although the somatic mutational profiles of gliomas between East Asians and non-East Asians were broadly consistent, a lower incidence of EGFR amplification in glioblastoma and a higher incidence of 1p19q-IDH-TERT triple-negative low-grade glioma were observed in East Asian cohorts. By summarizing large-scale disease surveillance, germline, and somatic genomic studies, this review reveals the unique characteristics of adult diffuse glioma among East Asians, to guide clinical management and policy design focused on patients with East Asian ancestry.

Genome-Wide Association Study for eGFR in a Taiwanese Population.

Chronic kidney disease (CKD) is a global public health issue associated with large economic burdens. CKD contributes to higher risks of cardiovascular complications, kidney failure, and mortality. The incidence and prevalence rates of kidney failure in Taiwan have remained the highest in the world. Assessing genetic factors that influence kidney function in specific populations has substantial clinical relevance. We investigated associations of genetic variants with eGFR. The quality control filtering and genotype imputation resulted in 10,008 Taiwan Biobank participants and 6,553,511 variants for final analyses. We examined these loci with in silico replication in individuals of European and African ancestry. Our results revealed one significant locus (4q21.1) and three suggestive significant loci (17q23.2, 22q13.2, and 3q29) for eGFR in the Taiwanese population. In total, four conditional-independent single nucleotide polymorphisms were identified as the most important variants within these regions, including rs55948430 (Coiled-Coil Domain Containing 158), rs1010269 (BCAS3), rs56108505 (MKL1), and rs34796810 (upstream of DLG1). By performing a meta-analysis, we found that the 4q21.1 and 17q23.2 loci were successfully replicated in the European population, whereas only the 17q23.2 locus was replicated in African ancestry. Therefore, these two loci are suggested to be transethnic loci, and the other two eGFR-associated loci (22q13.2 and 3q29) are likely population specific. We identified four susceptibility loci on 4q21.1, 17q23.2, 22q13.2, and 3q29 that associated with kidney-related traits in a Taiwanese population. The 22q13.2 (MKL1) and 3q29 (DLG1) were prioritized as critical candidates. Functional analyses delineated novel pathways related to kidney physiology in Taiwanese and East Asian ancestries.

RF10 | PMON217 Replication of PCOS Reproductive and Metabolic Subtypes in Diverse Cohorts – Towards a Rationale Approach to PCOS Classification

Abstract PCOS diagnosed by NIH or non-NIH Rotterdam criteria or by self-report is generally genetically similar. Using Hierarchical Clustering (HC), we have previously identified discrete, stable PCOS subtypes, which we designated reproductive (higher LH, FSH, SHBG) and metabolic (higher BMI, insulin, glucose), in a United States (US) cohort of ∼900 PCOS diagnosed by NIH criteria (Dapas et al. PLoS Med, 2020). The subtypes appeared to capture biologically meaningful differences because they were associated with distinct and novel genome-wide significant loci. In this study, we tested the hypothesis that the subtypes are a common feature of PCOS in regionally and ethnically diverse cohorts. All PCOS cases were ages 13-45 years, at least 2-years postmenarche and fulfilled NIH diagnostic criteria: 1) US European ancestry (EA), 1449; 2) Netherlands (NL) EA, 1067; 3) Greece (GR) EA, 568; 4) South Korea (KR) East Asian ancestry, 418. BMI, testosterone, SHBG, DHEAS, LH, FSH, fasting insulin, and fasting glucose levels were used for clustering. Trait Z-scores were compared among the cohorts. HC was adjusted for age and assay method. Both median BMI and BMI categories (nonobese, overweight, obese) defined by ancestry-specific cut points for EA and Asians differed (US&amp;gt;NL&amp;gt;GR&amp;gt;KR, all P&amp;lt;0.01). The prevalence of Class 2 (35.0-39.9) and Class 3 (≥ 40.0) was highest in US (P&amp;lt;0.001). The remaining traits were similar between cohorts prior to HC. Reproductive and metabolic subtypes were present in the 4 cohorts with similar Jaccard coefficients indicating cluster stability. The percent of cases was: reproductive subtype US 26%; NL 19%; GR, 62%; KR 20%; metabolic subtype US 53%; NL 61%; GR 22%; KR 31%. These differences were significant, except for the reproductive subtype in NL and KR. There was a 3-fold higher prevalence of the reproductive subtype in GR. BMI could not completely account for the metabolic subtype differences since KR had a higher prevalence of the metabolic subtype than GR, despite being significantly less obese. Remaining cases in each cohort who did not have a distinct pattern of trait distribution were designated "indeterminate" (US 21%; NL 20%; GR 16%; KR 49%). Reproductive and metabolic subtypes of PCOS diagnosed by NIH criteria are present in both regionally (US, Northern and Southern Europe) and ethnically (European and East Asian) diverse cohorts. Despite similar trait values, except for BMI, the prevalence of these subtypes varied among cohorts. Compared to other European and East Asian ancestry cohorts, the GR cohort had a strikingly higher prevalence of the reproductive and lower prevalence of the metabolic subtype. The reasons for these differences are being investigated but may reflect population-specific genetic variation. Nevertheless, our findings suggest that clustering algorithms capture biologically discrete subtypes in diverse PCOS populations diagnosed by NIH criteria. Presentation: Saturday, June 11, 2022 1:54 p.m. - 1:59 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis

Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls. The cohort comprised 122 individuals with IgA glomerulonephritis including 89 males (73%), 49 individuals (40%) of East Asian or Southern European ancestry, with an overall median age of 54 years (34–64), and median disease duration of 9 years (4–17). Thirty-nine (33%) had an eGFR < 60 ml/min/1.73 m2 and 72 had previously reached kidney failure (61%). Overall mean drusen counts were higher in IgA glomerulonephritis (9 ± 27) than controls (2 ± 7, p < 0.001). Central counts ≥ 10 were also more common (OR = 3.31 (1.42–7.73, p = 0.006), and were associated with longer disease duration (p = 0.03) but not kidney failure (p = 0.31). Larger drusen were associated with more mesangial IgA staining (p = 0.004). Increased drusen counts were also present in IgA glomerulonephritis secondary to Crohn’s disease but not with Henoch-Schonlein purpura. The finding of retinal drusen in IgA glomerulonephritis is consistent with complement activation and represents a model for better understanding glomerular immune deposition and a supporting argument for treatment with anti-complement therapies.

Genome-wide association study for systemic lupus erythematosus in an egyptian population.

Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians-an admixed North African/Middle Eastern population-using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 109). We identified a novel genome-wide significant locus near IRS1/miR-5702 (Pcorrected = 1.98 × 10-8) and eight novel suggestive loci (Pcorrected < 1.0 × 10-5). We also replicated (Pperm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r 2 > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10-95 < p < 1.0 × 10-2) across diverse tissues. These loci are involved in cellular proliferation and invasion-pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.

Proportion of stroke types in Madagascar: A tertiary-level hospital-based case series.

Like other countries in sub-Saharan Africa, Madagascar has a high burden of stroke. The Malagasy population is unique in sharing both African and Asian ancestry. The proportion of ischemic and hemorrhagic stroke types is unknown for this population. Our aim was to establish the proportion of stroke types and known risk factors for the Malagasy population. We conducted a single-center, tertiary-level hospital-based case series. We included all patients with a CT-imaging confirmed stroke who presented at the emergency ward of the study hospital between January 1, 2017, and November 20, 2018. Of 223 patients with CT-confirmed stroke, 57.4% (128/223, 95% CI: 51-64%) had an ischemic stroke and 42.6% (95/223, 95% CI: 36-49%) had an intracranial hemorrhage. The majority (89.5%; 85/95, 95% CI: 83-96%) of intracranial hemorrhages were intracerebral; 4.2% (4/95, 95% CI: 0-8%) had a subdural hematoma, 5.3% (5/95, 95% CI: 1-10%) had a subarachnoid hemorrhage, there was one isolated intraventricular hemorrhage (1.1%; 1/95, 95% CI: -1-3%). The prevalence of hypertension among stroke patients was high (86.6%; 187/216, 95% CI: 82-91%). Our study is the first to report the proportion of stroke types and known risk factors in Madagascar. We find that the proportion of hemorrhagic strokes was unexpectedly higher than that reported from other countries in sub-Saharan Africa. Our findings highlight the need for a country-specific approach to stroke prevention, treatment, and rehabilitation and provide guidance on public health resource allocation in Madagascar.

The construction of cross-population polygenic risk scores using transfer learning

As most existing genome-wide association studies (GWASs) were conducted in European-ancestry cohorts, and as the existing polygenic risk score (PRS) models have limited transferability across ancestry groups, PRS research on non-European-ancestry groups needs to make efficient use of available data until we attain large sample sizes across all ancestry groups. Here we propose a PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PRS model from an ancestry group with large sample GWASs to the dataset of target ancestry. In our application of constructing PRS for seven quantitative and two dichotomous traits for 10,285 individuals of South Asian ancestry and 8,168 individuals of African ancestry in UK Biobank, TL-PRS using PRS-CS as a baseline method obtained 25% average relative improvement for South Asian samples and 29% for African samples compared to the standard PRS-CS method in terms of predicted R2. Our approach increases the transferability of PRSs across ancestries and thereby helps reduce existing inequities in genetics research.

Genetic variation rs6795970 of the SCN10A gene is associated with PR interval in young population of Republic of Moldova

Abstract Background/Objectives The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction time. Prolongation of the PR interval increase risk of atrial fibrillation (AF) and heart block. Genome-wide association studies (GWAS) have identified association of a nonsynonymous single nucleotide polymorphism (SNP), rs6795970, in the SCN10A gene with PR interval in individuals of European and Asian ancestry. The aim of the study was to determine distribution of the genetic variants of rs6795970, associated with PR interval in young population of Republic of Moldova. Methods 1380 young participants from Republic of Moldova aged between 19–25 years, were genotyped for rs6795970 in the SCN10A gene, using TaqMan SNP Genotyping Assay. Results The genotype G/G, A/G, A/A distributions of rs6795970 among participants were 37%, 48%, 15%, respectively (χ2=0.086, p=0.770). The allele frequencies for G and A, in young participants were 61% and 39%, respectively. We observed association between rs6795970_A and a prolongation of the PR interval (p=0.003). Conclusions In our study, we determined that distribution of the genetic variants of rs6795970, associated with PR interval in young population of Republic of Moldova was consistent with 1000 Genomes data in the European population. Therefore, our data demonstrate that the A allele is associated with prolongation of the PR interval and at least 15% of all participants (the A/A genotype), may have an increased risk of conduction abnormalities. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National project “Study of molecular genetic polymorphism of metabolic risk factors in young population of the Republic of Moldova National project “Identification and validation of genetic and epigenetic biomarkers in chronic non-communicable diseases with major impact on public health”

Ethnic, gender and other sociodemographic biases in genome-wide association studies for the most burdensome non-communicable diseases: 2005-2022.

Since 2005, disease-related human genetic diversity has been intensively characterized using genome-wide association studies (GWAS). Understanding how and by whom this work was performed may yield valuable insights into the generalizability of GWAS discoveries to global populations and how high-impact genetics research can be equitably sustained in the future. We mined the NHGRI-EBI GWAS Catalog (2005-2022) for the most burdensome non-communicable causes of death worldwide. We then compared (i) the geographic, ethnic and socioeconomic characteristics of study populations; (ii) the geographic and socioeconomic characteristics of the regions within which researchers were located and (iii) the extent to which male and female investigators undertook and led the research. The research institutions leading the work are often US-based (37%), while the origin of samples is more diverse, with the Nordic countries having contributed as much data to GWAS as the United States (~17% of data). The majority of first (60%), senior (75%) and all (66%) authors are male; although proportions vary by disease and leadership level, male co-authors are the ubiquitous majority. The vast majority (91%) of complex trait GWAS has been performed in European ancestry populations, with cohorts and scientists predominantly located in medium-to-high socioeconomically ranked countries; apart from East Asians (~5%), other ethnicities rarely feature in published GWAS. See: https://hugofitipaldi.shinyapps.io/gwas_results/ to browse all results. Most GWAS cohorts are of European ancestry residing outside the United States, with a smaller yet meaningful proportion of East Asian ancestry. Papers describing GWAS research are predominantly authored by male scientists based in medium-to-high income countries.

The importance of ancestry to understanding tumor mutation burden in cancer.

In the current issue of Cancer Cell, Nassar and colleagues find that in solid tumors, tumor-only sequencing leads to an overestimate of the biomarker tumor mutation burden (TMB), particularly in patients of African or Asian ancestry. Correction of the TMB estimate improves the correlation between TMB and response to immunotherapy.

A healthy plant–based diet is favorably associated with cardiometabolic risk factors among participants of South Asian ancestry

Plant-based diets are recommended for chronic disease prevention, yet there has been little focus on plant-based diet quality among participants of South Asian ancestry who consume a predominantly plant-based diet. We evaluated cross-sectional and prospective associations between plant-based diet quality and cardiometabolic risks among participants of South Asian ancestry who are living in the United States. We included 891 participants of South Asian ancestry who completed the baseline visit in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. The prospective analysis included 735 participants who completed exam 2 (∼5 years after baseline). The plant-based diet quality was assessed using 3 indices: an overall plant-based diet index (PDI) that summarizes the consumption of plant foods, a healthy PDI (hPDI) that measures consumption of healthy plant foods, and an unhealthy PDI (uPDI) that reflects consumption of less healthy plant foods. At baseline, the PDI score was inversely associated with fasting glucose. We observed inverse associations between PDI and hPDI scores and HOMA-IR, LDL cholesterol, weight, and BMI (all P values<0.05). Higher scores on the hPDI, but not PDI, were associated with lower glycated hemoglobin, higher adiponectin, a smaller visceral fat area, and a smaller pericardial fat volume. Each 5-unit higher hPDI score was associated with lower likelihoods of fatty liver (OR: 0.76; 95% CI: 0.64, 0.90) and obesity (OR: 0.88; 95% CI: 0.80, 0.97). There were no associations between uPDI scores and cardiometabolic risks. Prospectively, after covariate adjustment for baseline values, each 5-unit higher hPDI score was associated with an 18% lower risk of incident type 2 diabetes (OR: 0.82; 95% CI: 0.67, 1.00). A higher intake of healthful plant-based foods was associated with a favorable cardiometabolic risk profile. Dietary recommendations to lower chronic disease risks among participants of South Asian ancestry should focus on the quality of plant-based foods.

Whole-genome sequencing of East Asian lung cancers reveals new germline pathogenic variants.

In this issue of Cancer Cell, Wang etal. use whole-genome sequencing of lung cancer cases and controls with East Asian ancestry to comprehensively characterize both common and rare variants that predispose to lung cancer. Their findings suggest that rare promoter variants in BRCA2 are associated with increased lung cancer risk.