scholarly journals Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study

2021 ◽  
Author(s):  
VT Nguyen ◽  
A Braun ◽  
J Kraft ◽  
TMT Ta ◽  
GM Panagiotaropoulou ◽  
...  
Keyword(s):  
Pilot Study ◽  
Data Collection ◽  
Predictive Power ◽  
Association Studies ◽  
East Asian ◽  
Genetic Research ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractObjectivesGenome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.MethodsIn a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.ResultsSCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.DiscussionOur results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

scholarly journals Polygenic transcriptome risk scores (PTRS) can improve portability of polygenic risk scores across ancestries

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Yanyu Liang ◽  
Milton Pividori ◽  
Ani Manichaikul ◽  
Abraham A. Palmer ◽  
Nancy J. Cox ◽  
...  
Keyword(s):  
Association Studies ◽  
Poor Performance ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Transcript Levels ◽  
Polygenic Risk ◽  
Genome Wide

Abstract Background Polygenic risk scores (PRS) are valuable to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry leading to poor performance in populations of non-European ancestry. Results We introduce the polygenic transcriptome risk score (PTRS), which is based on predicted transcript levels (rather than SNPs), and explore the portability of PTRS across populations using UK Biobank data. Conclusions We show that PTRS has a significantly higher portability (Wilcoxon p=0.013) in the African-descent samples where the loss of performance is most acute with better performance than PRS when used in combination.

scholarly journals Identification of type 2 diabetes loci in 433,540 East Asian individuals

2019 ◽  
Author(s):  
Cassandra N Spracklen ◽  
Momoko Horikoshi ◽  
Young Jin Kim ◽  
Kuang Lin ◽  
Fiona Bragg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Abstract P225: African American LDL-C GWAS Reveals a Strong Protective SNP Association in APOE; The eMERGE Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Laura J Rasmussen-Torvik ◽  
Jennifer A Pacheco ◽  
M G Hayes ◽  
Abel N Kho ◽  
Arun Muthalagu ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Electronic Medical Records ◽  
Effect Size ◽  
Medical Records ◽  
Association Studies ◽  
Genetic Research ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Several Genome-Wide Association Studies (GWAS) of LDL-C have been published in populations of European-Ancestry but only one previous GWAS of LDL-C has been published in African Americans. Using phenotype data extracted from repeated lab measurements of LDL-C in electronic medical records (EMR) and the Illumina 1M Duo array we performed a LDL-C GWAS in African Americans in the eMERGE study. Methods: African Americans from eMERGE sites Northwestern University and Vanderbilt University were included in the analysis. All available LDL-C measurements as well as information about statin and hormone prescriptions, cancer, diabetes, and hypo/hyperthyroidism were abstracted from electronic medical records. Two separate samples were created; a sample incorporating exclusions due to medication use and disease diagnoses (n = 618) and a sample without exclusions (n = 1249). After data extraction and cleaning, median LDL-C for each individual was used for both analyses. GWAS analysis of median LDL-C was conducted using PLINK, controlling for age, age2, sex, recruitment site, genotyping batch, and the first three principal components of ancestry. Results: One SNP was significantly (p < 5 X 10-8) associated with LDL-C in both samples; rs7412 in the APOE gene. In the sample excluding measurements taken from those on medication or with prevalent disease, the effect size of this association was large compared to SNPs identified in previous GWAS results for LDL-C (a decrease of 19.9 mg/dl per one additional copy of the minor allele, p = 8.7 x 10 -11). The percent of LDL-C variance accounted for by rs7412 in this sample was 6.7%. The effect size of the rs7412 association was smaller in the sample without exclusions (a decrease of 12.3 mg/dl in LDL-C per allele, p = 1.6 x 10 -9) but still large compared to other LDL-C GWAS findings. Effect sizes for SNPs previously identified in the other African American GWAS of LDL-C were consistent with the earlier report, although there was not sufficient power for these associations to achieve genome-wide significance in this population. Discussion: SNP rs7412 appears to be an important common genetic variant influencing LDL-C levels. Although other signals in APOE have been detected in previous GWAS of European-Ancestry populations and African Americans and this specific SNP has been reported in several previous candidate gene studies, this association has not been identified previously in GWAS likely because rs7412 (or a good proxy) was not included on the genotyping arrays used in these studies. Our results (a) indicate that the association of rs7412 and LDL-C should be examined in other larger African American study populations, (b) further validate the use if EMR-derived traits in genetic research and (c) suggest one should be cautious in concluding that currently published GWAS have discovered all important common genetic variation contributing to certain disease traits.

scholarly journals Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215624
Author(s):  
Sinjini Sikdar ◽  
Annah B Wyss ◽  
Mi Kyeong Lee ◽  
Thanh T Hoang ◽  
Marie Richards ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Genetic Risk ◽  
Association Studies ◽  
European Ancestry ◽  
Risk Scores ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Genetic Risk Scores ◽  
Genome Wide

RationaleGenome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few.MethodsWe analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.ResultsEach trait was highly significantly associated with its GRS (all three p values<8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin.ConclusionsEvaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

scholarly journals On cross-ancestry cancer polygenic risk scores

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009670
Author(s):  
Lars G. Fritsche ◽  
Ying Ma ◽  
Daiwei Zhang ◽  
Maxwell Salvatore ◽  
Seunggeun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
South Asian ◽  
Disease Risk ◽  
Association Studies ◽  
East Asian ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Target Sample

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

scholarly journals Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci

2019 ◽  
Vol 49 (3) ◽  
pp. 193-202
Author(s):  
Chris H.L. Thio ◽  
Anna Reznichenko ◽  
Peter J. van der Most ◽  
Zoha Kamali ◽  
Ahmad Vaez ◽  
...  
Keyword(s):  
Kidney Function ◽  
Association Studies ◽  
Serum Magnesium ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Serum Urea ◽  
Genome Wide ◽  
European Populations

Background: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. Methods: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. Results: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. Conclusions: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

scholarly journals Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

2021 ◽  
Author(s):  
Louise Wang ◽  
Heena Desai ◽  
Shefali S. Verma ◽  
Anh Le ◽  
Ryan Hausler ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Genetic Factors ◽  
Association Studies ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Discriminatory Ability ◽  
Polygenic Risk ◽  
Genome Wide ◽  
European Populations

Purpose: Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) significantly associated with several cancers, but the predictive ability of polygenic risk scores (PRS) derived from multiple variants is unclear for many cancers, especially among non-European populations. Methods: Genome wide genotype data was available for 20,079 individuals enrolled in an academic biobank. PRS were derived from significant DNA variants for 15 cancers. Logistic regression was used to determine the discriminatory accuracy of each cancer-specific PRS in patients of genetically determined African and European ancestry separately. Results: Among European individuals, four PRS were significantly associated with their respective cancers (breast, colon, melanoma, and prostate), with an OR ranging from 1.25-1.47. Among African individuals, PRS for breast, colon, and prostate were significantly associated with their respective cancers. The discriminatory ability of a model comprised of age, sex, and principal components was 0.617–0.709, and the AUC increased by 1-4% with the addition of the PRS in Europeans. AUC was overall higher in the full model including PRS (AUC 0.742-0.818) in African individuals, but the PRS increased the AUC by less than 1% in the majority of cancers in African individuals. Conclusion: PRS constructed from SNPs moderately increased discriminatory ability for cancer status over age, sex, and nonspecific genetic factors in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors for cancer risk in non-European populations to incorporate PRS into cancer risk assessment.

Genome-wide association studies promise to discover novel indicators of hypertension. Endothelin-related SNPs are currently in clinical trials

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Association Studies ◽  
Genetic Research ◽  
Health Inequity ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Functional Studies ◽  
Genome Wide ◽  
Genetic Results

Nevertheless, in the field of hypertension genomics, it is likely that new genetic markers will be identified, but until they are, the results are restricted. Following on from this, and by drawing from pharmacogenomic, pleiotropic, and functional studies, the follow-up and clinical translation of these genetic results seems to be very promising. These endothelin-related SNPs, which have gone on to the clinical trial stage, signify further success in the advancement of hypertension precision medicine that has already been discovered through genetic research. Although the use of polygenic risk scores may appear advantageous, further study is required to verify their effectiveness, and this issue must be examined further to determine the potential for these scores to lead to an increase in health inequity.

scholarly journals On Cross-ancestry Cancer Polygenic Risk Scores

2021 ◽  
Author(s):  
Lars G. Fritsche ◽  
Ying Ma ◽  
Daiwei Zhang ◽  
Maxwell Salvatore ◽  
Seunggeun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
South Asian ◽  
Disease Risk ◽  
Association Studies ◽  
East Asian ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Target Sample

AbstractPolygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

scholarly journals Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

2021 ◽  
Vol 11 ◽  
Author(s):  
Ye Lu ◽  
Manuel Gentiluomo ◽  
Angelica Macauda ◽  
Domenica Gioffreda ◽  
Maria Gazouli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Risk ◽  
Genetic Model ◽  
Association Studies ◽  
European Ancestry ◽  
Risk Scores ◽  
Cancer Case ◽  
Genome Wide Association Studies ◽  
Pancreatic Cancer Risk ◽  
Genome Wide

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p&lt;10−5) compared with the additive effects (p&gt;10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p &lt; 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Sign in / Sign up

Export Citation Format

Share Document