non-European Ancestry Populations Research Articles

Identifying Rare Genetic Determinants for Improved Polygenic Risk Prediction of Bone Mineral Density and Fracture Risk.

Osteoporosis and fractures severely impact the elderly population. Polygenic risk scores for bone mineral density have demonstrated potential clinical utility. However, the value of rare genetic determinants in risk prediction has not been assessed. With whole-exome sequencing data from 436,824 UK Biobank participants, we assigned White British ancestry individuals into a training data set (n = 317,434) and a test data set (n = 74,825). In the training data set, we developed a common variant-based polygenic risk score for heel ultrasound speed of sound (SOS). Next, we performed burden testing to identify genes harboring rare determinants of bone mineral density, targeting influential rare variants with predicted high deleteriousness. We constructed a genetic risk score, called ggSOS, to incorporate influential rare variants in significant gene burden masks into the common variant-based polygenic risk score. We assessed the predictive performance of ggSOS in the White British test data set, as well as in populations of non-White British European (n = 18,885), African (n = 7165), East Asian (n = 2236), South Asian (n = 9829), and other admixed (n = 1481) ancestries. Twelve genes in pivotal regulatory pathways of bone homeostasis harbored influential rare variants associated with SOS (p < 5.5 × 10-7 ), including AHNAK, BMP5, CYP19A1, FAM20A, FBXW5, KDM5B, KREMEN1, LGR4, LRP5, SMAD6, SOST, and WNT1. Among 4013 (5.4%) individuals in the test data set carrying these variants, a one standard deviation decrease in ggSOS was associated with 1.35-fold (95% confidence interval [CI] 1.16-1.57) increased hazard of major osteoporotic fracture. However, compared with a common variant-based polygenic risk score (C-index = 0.641), ggSOS had only marginally improved prediction accuracy in identifying at-risk individuals (C-index = 0.644), with overlapping confidence intervals. Similarly, ggSOS did not demonstrate substantially improved predictive performance in non-European ancestry populations. In summary, modeling the effects of rare genetic determinants may assist polygenic prediction of fracture risk among carriers of influential rare variants. Nonetheless, improved clinical utility is not guaranteed for population-level risk screening. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Landscape of Monogenic Parkinson's Disease in Populations of Non-European Ancestry: A Narrative Review.

There has been a bias in the existing literature on Parkinson's disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD patients of non-European or mixed ancestry. We reviewed articles published during the 2000-2023 period, focusing on the genetic status of PD patients of non-European origin (Indian, East and Central Asian, Latin American, sub-Saharan African and Pacific islands). There were substantial differences regarding monogenic PD forms between patients of European and non-European ancestry. The G2019S Leucine Rich Repeat Kinase 2 (LRRK2) mutation was rather scarce in non-European populations. In contrast, East Asian patients carried different mutations like p.I2020T, which is common in Japan. Parkin (PRKN) variants had a global distribution, being common in early-onset PD in Indians, in East Asians, and in early-onset Mexicans. Furthermore, they were occasionally present in Black African PD patients. PTEN-induced kinase 1 (PINK1) and PD protein 7 (DJ-1) variants were described in Indian, East Asian and Pacific Islands populations. Glucocerebrosidase gene variants (GBA1), which represent an important predisposing factor for PD, were found in East and Southeast Asian and Indian populations. Different GBA1 variants have been reported in Black African populations and Latin Americans. Existing data reveal a pronounced heterogeneity in the genetic background of PD. A number of common variants in populations of European ancestry appeared to be absent or scarce in patients of diverse ethnic backgrounds. Large-scale studies that include genetic screening in African, Asian or Latin American populations are underway. The outcomes of such efforts will facilitate further clinical studies and will possibly contribute to the identification of either new pathogenic mutations in already described genes or novel PD-related genes.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? Genetic instruments suggest that higher fasting insulin may increase infertility in women. Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. Treatments for lower fasting insulin levels may reduce the risk of infertility in women. The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. N/A.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.

Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study.

While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort. The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

Interethnic Differences in Bladder Cancer Incidence and the Association between Type 2 Diabetes and Bladder Cancer in the Multiethnic Cohort Study.

Research on the association between type 2 diabetes (T2D) and bladder cancer (BCA) risk among non-European ancestry populations is sparse to nonexistent, and most prior studies rely on a single baseline assessment of T2D status. We estimated the T2D-BCA association using the Multiethnic Cohort Study of 185,059 men and women in California and Hawaii. Participants were African American, European American, Japanese American, Latin American, and Native Hawaiian, ages 45-75 years at enrollment (1993-1996). T2D was assessed by self-report at baseline, follow-up surveys, and Medicare claims. Cases were identified using Surveillance, Epidemiology and End Results Program cancer registries through 2016. Associations were estimated by race/ethnicity using Cox proportional hazards regression. Adjusted attributable fractions (AAF) and cumulative absolute risk of bladder cancer were estimated across groups. Over an average 19.7 years of follow-up 1,890 incident bladder cancer cases were diagnosed. Time-varying T2D was associated with bladder cancer in the multiethnic sample (HR = 1.17; 95% confidence interval, 1.05-1.30); however, the HR did not differ by race/ethnicity (P = 0.85). The AAF was 4.2% in the multiethnic sample and largest among Native Hawaiians (9.8%). Absolute risk of bladder cancer among European Americans without T2D was higher than all other groups with T2D. T2D is significantly associated with bladder cancer risk in a multiethnic sample. Those with T2D have higher incidence of bladder cancer, regardless of racial/ethnic group. Reducing T2D prevalence could substantially lower bladder cancer incidence among Native Hawaiians due to T2D being more common in this group. High absolute risk of bladder cancer among European Americans, regardless of T2D status, indicates that elevated bladder cancer risk in this group may be due to factors other than T2D. Future studies must explore reasons for this difference in incidence.

Abstract 6461: Excess risk due to smoking and modifying effect of quitting on bladder cancer incidence: the multiethnic cohort

Abstract Background: Smoking is an established risk factor for urothelial cancer of the bladder (BC), attributed to over 50% of cases among men, however associations outside of European-descent populations are infrequently reported. Further, absolute risk of BC by smoking history has not yet been reported. Characterizing these associations will identify value of smoking cessation across non-European ancestry populations. Methods: We estimated the association between pack-years, years quit, and BC among 181,231 Multiethnic Cohort Study participants from five major racial/ethnic groups (African Americans [AA], European Americans [EA], Japanese Americans [JA], Latinos [LA], Native Hawaiians [NH]) 45-75 years old at enrollment (1993-1996). Smoking history was assessed by self-report at cohort entry and on a follow-up survey (2003-2008). Associations were estimated using an excess relative risk model to distinguish between variables that affect baseline risk and variables (e.g. years quit) that only affect excess risk due to smoking, while adjusting for sex, age, race/ethnicity, diabetes, body mass index, and cigarettes smoked per day. BC cases were identified through SEER cancer registries to 2017. We tested for heterogeneity of smoking variables by race/ethnicity and estimated incidence across age, race-ethnicity, pack-years, and years quit. Results: Over a mean 19 years of follow-up, 1,914 BC cases were identified. Age-standardized incidence rates of BC were highest among EA (51/100,000) and lowest among LA (24/100,000). Never smokers were most common among JA and LA (51%) and least common in other racial/ethnic groups (39-40%). In the full study sample, 50 pack-years smoked was associated with BC (HR=3.2 95% CI 2.7, 3.6). The association was heterogeneous by race/ethnicity (p=0.02) and statistically significant within each racial/ethnic group (p&amp;lt;0.05), except NH (p=0.07). Associations were strongest among EA (HR=4.0), followed by AA (HR=3.6), JA (HR=2.7), LA (HR=2.6), and NH (HR=2.4). There was no statistically significant heterogeneity of smoking cessation (p=0.08) or cigarettes smoked per day (p=0.82) by race/ethnicity. Each year quit resulted in a less than 1% decrease in the excess relative risk from smoking (p=0.12). The absolute risk models showed highest incidence at age 70 among EA current smokers (176/100,000) and lowest among AA never smokers (27/100,000). At age 70, current smokers across all ethnic groups had lower risk than EA who quit at age 45. Conclusion: Pack-years smoked is significantly associated with BC risk. EA and AA groups experience the greatest excess relative risk from smoking and NH the lowest. Reduction in excess relative risk following smoking cessation is weak, meaning the cumulative effect of pack-years smoked on BC risk cannot easily be attenuated with quitting. This contrasts with the risk reduction seen for lung and pancreatic cancer. Citation Format: David Bogumil, Victoria Cortessis, Daniel Stram, Veronica W. Setiawan, Christopher Haiman, Loic Le Marchand, Gertraud Maskarinec. Excess risk due to smoking and modifying effect of quitting on bladder cancer incidence: the multiethnic cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6461.

The complex genetic architecture of Alzheimer's disease: novel insights and future directions.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations. Two new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563-with an effective sample size of 332,376-by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. WHERE NEXT?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-β and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

Epigenetic biomarkers for smoking cessation

Cigarette smoking has been associated with epigenetic alterations that may be reversible upon cessation. As the most-studied epigenetic modification, DNA methylation is strongly associated with smoking exposure, providing a potential mechanism that links smoking to adverse health outcomes. Here, we reviewed the reversibility of DNA methylation in accessible peripheral tissues, mainly blood, in relation to cigarette smoking cessation and the utility of DNA methylation as a biomarker signature to differentiate current, former, and never smokers and to quantify time since cessation. We summarized thousands of differentially methylated Cytosine-Guanine (CpG) dinucleotides and regions associated with smoking cessation from candidate gene and epigenome-wide association studies, as well as the prediction accuracy of the multi-CpG predictors for smoking status. Overall, there is robust evidence for DNA methylation signature of cigarette smoking cessation. However, there are still gaps to fill, including (1) cell-type heterogeneity in measuring blood DNA methylation; (2) underrepresentation of non-European ancestry populations; (3) limited longitudinal data to quantitatively measure DNA methylation after smoking cessation over time; and (4) limited data to study the impact of smoking cessation on other epigenetic features, noncoding RNAs, and histone modifications. Epigenetic machinery provides promising biomarkers that can improve success in smoking cessation in the clinical setting. To achieve this goal, larger and more-diverse samples with longitudinal measures of a broader spectrum of epigenetic marks will be essential to developing a robust DNA methylation biomarker assay, followed by meeting validation requirements for the assay before being implemented as a clinically useful tool.

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson’s disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10−9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10−8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14–0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.

An empirical Bayes approach to improving population-specific genetic association estimation by leveraging cross-population data.

Populations of non-European ancestry are substantially underrepresented in genome-wide association studies (GWAS). As genetic effects can differ between ancestries due to possibly different causal variants or linkage disequilibrium patterns, a meta-analysis that includes GWAS of all populations yields biased estimation in each of the populations and the bias disproportionately impacts non-European ancestry populations. This is because meta-analysis combines study-specific estimates with inverse variance as the weights, which causes biases towards studies with the largest sample size, typical of the European ancestry population. In this paper, we propose two empirical Bayes (EB) estimators to borrow the strength of information across populations although accounting for between-population heterogeneity. Extensive simulation studies show that the proposed EB estimators are largely unbiased and improve efficiency compared to the population-specific estimator. In contrast, even though the meta-analysis estimator has a much smaller variance, it yields significant bias when the genetic effect is heterogeneous across populations. We apply the proposed EB estimators to a large-scale trans-ancestry GWAS of stroke and demonstrate that the EB estimators reduce the variance of the population-specific estimator substantially, with the effect estimates close to the population-specific estimates.

Towards a global view of multiple sclerosis genetics.

Multiple sclerosis (MS) is a neuroimmunological disorder of the CNS with a strong heritable component. The genetic architecture of MS susceptibility is well understood in populations of European ancestry. However, the extent to which this architecture explains MS susceptibility in populations of non-European ancestry remains unclear. In this Perspective article, we outline the scientific arguments for studying MS genetics in ancestrally diverse populations. We argue that this approach is likely to yield insights that could benefit individuals with MS from all ancestral groups. We explore the logistical and theoretical challenges that have held back this field to date and conclude that, despite these challenges, inclusion of participants of non-European ancestry in MS genetics studies will ultimately be of value to all patients with MS worldwide.

Abstract 734: History of diabetes is differentially associated with urothelial cancer risk in understudied racial/ethnic groups in the Multiethnic Cohort Study (MEC)

Abstract Background: Type 2 diabetes (T2D) is an established risk factor for urothelial cancer (UC), however there is very little data characterizing this association in populations of non-European ancestry. Understanding the relationship between T2DM and UC across multiple populations is important since both risk and severity of each condition differ according to race and ethnicity. Methods: We estimated the association between T2D and UC among 185,587 MEC participants who were between 45 and 75 years old at enrollment (1993-1996) and from five major racial/ethnic groups (African Americans, Japanese Americans, Native Hawaiians, Latinos, and non-Hispanic whites). T2D status was assessed by self-report at cohort entry. UC cases were identified through linkages to statewide SEER cancer registries. We estimated the association between T2D and UC using Cox regression, adjusting for known confounders (smoking duration, smoking intensity, alcohol consumption, body mass index), stratifying on sex, age, and ethnicity. Using the full model, we assessed heterogeneity of associations by race/ethnicity. Results: Over a mean of 19 years of follow-up, 2,398 incident UC cases were identified. The prevalence of T2D was highest among African Americans (15.7%), followed by Latinos (15.6%), Native Hawaiians (14.8%), Japanese Americans (10.5%), and non-Hispanic whites (5.9%). The age-standardized UC incidence rates were highest among whites (60/100,000) followed by Japanese Americans (42/100,000), Native Hawaiians (40/100,000), African Americans (37/100,000), and Latinos (29/100,000). Incidence of UC was 1.11 (95% CI: 0.97, 1.26)-fold greater in those who reported a history of T2D, and this association differed between racial-ethnic groups (pheterogeneity=0.04). Estimates of the association between T2D and UC achieved statistical significance among African Americans (HR=1.49; 95% CI: 1.12, 1.98) and Native Hawaiians (HR=1.68; 95% CI: 1.08, 2.60), but not among non-Hispanic whites (HR=1.06; 95% CI: 0.78, 1.43), Latinos (HR=0.96; 95% CI: 0.71, 1.29), or Japanese Americans (HR=0.95; 95% CI: 0.75, 1.21). Conclusions: In this multiethnic analysis, estimates of the association between T2DM and UC were strongest among African American and Native Hawaiian participants. The apparently stronger associations in these groups may be due to greater severity and/or poorer control of T2DM. African Americans and Native Hawaiians may benefit from targeted interventions to better manage T2D in these populations to reduce risk of UC. Citation Format: David Bogumil, Victoria Cortessis, Lynne Wilkens, Veronica Wendy Setiawan, Christopher Haiman, Loic Le Marchand, Gertraud Maskarinec. History of diabetes is differentially associated with urothelial cancer risk in understudied racial/ethnic groups in the Multiethnic Cohort Study (MEC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 734.

1273-P: The Interplay between Polygenic and Rare HNF1A Variant Risk in Type 2 Diabetes

Rare variants in HNF1A, a pancreatic beta cell transcription factor, have been shown to be associated with T2D and monogenic diabetes. Here, we examine the effect of functionally validated rare (MAF&amp;lt;1%) nonsynonymous variants (RNVs) in a functional domain of HNF1A on T2D risk, and whether their effect is influenced by an overall genetic susceptibility to T2D. Using exome sequencing data of 3,443 African ancestry (AA) and 157,182 European ancestry (EA) individuals in the UK Biobank and 5,018 AA, 5,6EA and 7,1Hispanic-Latino Ancestry (HA) individuals in the BioMe Biobank, we identified 132 AA, 287 EA, and 64 HA RNV carriers (NRNVs= 30) of HNF1A variants that impair protein function ≤ 60%. T2D Polygenic Risk Scores (PRSs) were built using either trans-ethnic or EA GWAS summary statistics and standardized per ancestry. We tested the association between RNV carrier status and the PRS with T2D risk, and meta-analyzed the ancestry-specific results. Carrying any of the HNF1A RNV mutations was associated with a 1.5 increase in the odds of T2D in the EA, albeit non-significantly (P=0.06) , but not in the AA (OR=1.1, P=0.6) or HA (OR=1 , P=1) . We then restricted analyses to RNVs within a functional domain, which results in more pronounced effects in the AA (OR=1.5, P=0.07) and EA (OR=1.9, P=0.002) but not in the HA (OR=0.8, P=0.5) . Per SD increase in the PRS, there is a significant 1.7, 1.6 and 2.1 higher odds of T2D in AA, EA and HA individuals, respectively. Even though we observed no interaction between the PRS and HNF1A RNVs (P &amp;gt;; 0.05) , the association between RNVs and T2D was more pronounced among EA individuals with a high PRS. Functional domain carriers (NEA = 50) in the top PRS quintile had a 3.6 (P=0.0008) higher odds of T2D as compared to non-carriers in the same quintile. Our study shows the value of large biobanks in studying rare variants, the importance of variant selection, and the need to include non-European ancestry populations. We demonstrate the utility of combining rare and common variant risks to better assess T2D risk. Disclosure L.Stalbow: None. M.H.Preuss: None. N.Chami: None. R.A.J.Smit: None. R.J.Loos: None.

The 90 plus: longevity and COVID-19 survival.

The world population is getting older and studies aiming to enhance our comprehension of the underlying mechanisms responsible for health span are of utmost interest for longevity and as a measure for health care. In this review, we summarized previous genetic association studies (GWAS) and next-generation sequencing (NGS) of elderly cohorts. We also present the updated hypothesis for the aging process, together with the factors associated with healthy aging. We discuss the relevance of studying older individuals and build databanks to characterize the presence and resistance against late-onset disorders. The identification of about 2 million novel variants in our cohort of more than 1000 elderly Brazilians illustrates the importance of studying highly admixed populations of non-European ancestry. Finally, the ascertainment of nonagenarians and particularly of centenarians who were recovered from COVID-19 or remained asymptomatic opens new avenues of research aiming to enhance our comprehension of biological mechanisms associated with resistance against pathogens.

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.

RIC3 variants are not associated with Parkinson's disease in large European, Latin American, or East Asian cohorts

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.