Population Architecture Using Genomics And Epidemiology Research Articles

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans

Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10-4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10-7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis.

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study

Correction to: Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium.

The authors regret that Yinchang Lu's name incorrectly included a middle initial in the author list. The details given in this erratum are correct.

Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium

Aims/hypothesisElevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies.MethodsA multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation.ResultsPreviously reported SNP associations were significantly replicated (p ≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513.Conclusions/interpretationThese findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries.Data availabilityThe summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p<0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

Abstract P104: Genetic Factors Influence Glycated Hemoglobin, Fasting Glucose, and Fasting Insulin Levels in the Population Architecture Using Genomics and Epidemiology Consortium

Elevated levels of fasting glucose and fasting insulin precede the development type 2 diabetes (T2D). While T2D and cardiovascular disease share common risk factors, dysregulation of glucose metabolism is of particular concern because it can result in end-organ damage including the heart, nerves, kidneys, and eyes. The prevalence of diabetes is higher in American minority populations. Through genome-wide association studies, approximately 60 loci have been identified for fasting glucose, fasting insulin, and glycated hemoglobin. To better understand the genetic basis of glucose dysregulation, the Population Architecture using Genomics and Epidemiology (PAGE) Consortium genotyped 12,801 Hispanic/Latinos, 5,696 African Americans, 1,405 Native Hawaiians, 398 Native Americans, and 1,727 Asians without diabetes using the approximately 1.3 million variants on the Multi-Ethnic Global Array (MEGA), which is enriched for coding variation and ancestral diverse content. Through ancestry-combined single variant association testing with fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c), we identified a novel potential association between decreased HbA1c and the minor A allele of rs11887523 ( p = 4.51x10 -9 , MFSD2B p.A60T, minor allele frequency (MAF) 7% in African Americans, MAF 2% in Hispanics). Other associations with HbA1c included hemoglobin genes, further highlighting the importance of considering variation in hemoglobin and red-blood cell lifespan when using HbA1c as a measure of glucose control. We also replicated several known associations including between fasting glucose and variants near G6PC2, GCKR, MTNR1B, and FOXA2 ; and between fasting insulin and the GRB14/COBLL1 locus. Further analyses including imputing the data out to 1000 Genomes phase3 and gene-based tests of rare variants are underway. These will increase power to detect associations with ancestry-specific rare variants.

Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium

Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

Background/ObjectivesCentral adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of BMI and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.Subjects/MethodsTo identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine mapping cardiovascular associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.ResultsOf the 17 WHR loci, eight SNPs located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.ConclusionsOf 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Abstract P256: Generalization and Fine Mapping of Genetic Associations with Hematocrit in Multi-ethnic Populations: The Population Architecture Using Genomics and Epidemiology (PAGE) Study

Introduction: Variability within the normal population range of hematocrit is associated with stroke and myocardial infarction. Published GWAS of hematocrit have identified multiple loci, yet few studies have included populations of Hispanic or African descent, thereby limiting opportunities to identify population-specific variants or narrow associated regions for functional analysis. We present a fine-mapping analysis of six previously identified hematocrit loci in African American and Hispanic/Latino participants of the PAGE study. Methods: Approximately 200,000 genotyped or imputed Metabochip variants were examined for association with hematocrit (proportion of whole blood comprising red blood cells) in 19,822 Hispanic/Latino and 19,973 African American participants. SNPs were excluded on a population-specific basis if effective heterozygosity was &lt; 30. Primary and conditional analyses were performed in Plink, ProbABEL, or SuGen; fixed-effects meta-analyses were performed in Metal. Trans-ethnic and ancestry-specific meta-analyses were performed in MANTRA to generate 99% credible intervals for previously published variants that generalized to our populations. Results: We first examined whether 8,261 variants in five previously identified hematocrit loci ( HFE , ABO , HK1 , SH2B3 / ATXN2 , and TMPRSS6 ) were associated with hematocrit in our study populations. Three loci generalized (p&lt;1.7x10 -4 ) to Hispanic/Latino participants ( ABO, HK1, and TMPRSS6 ) and three generalized to African Americans ( HFE , ABO , and SH2B3/ATXN2 ). Among generalized loci, conditional analyses adjusting for published variants in European-ancestry or East Asian populations did not identify any independently associated SNPs in Hispanic Latinos or African Americans (p&lt;1.3x10 -5 ). Trans-ethnic meta-analysis for the ABO locus resulted in a 5 SNP, 13kb 99% credible interval, shorter than both the Hispanic/Latino (17kb) and African American (360kb) credible intervals. In discovery analysis, we identified one variant associated with hematocrit in Hispanic/Latinos at array-wide significance levels ( PROX1 locus, p&lt;3.0x10 -7 ). No novel loci were identified in African Americans. Conclusion: Our findings provide evidence that the same genomic loci influence normal variation in hematocrit values across diverse ancestral populations. Trans-ethnic fine mapping of the gene-rich ABO locus—which has been associated with ischemic stroke, thrombosis, and myocardial infarction in addition to hematocrit GWA studies—suggests that a functional variant may reside in the first intron of the ABO coding region. Additionally, identification of previously unidentified associations in Hispanic/Latinos emphasizes the importance of including diverse populations in association studies as well as the potential to identify population-specific functional variants within known or discovery loci.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Extracting Primary Open-Angle Glaucoma from Electronic Medical Records for Genetic Association Studies.

Electronic medical records (EMRs) are being widely implemented for use in genetic and genomic studies. As a phenotypic rich resource, EMRs provide researchers with the opportunity to identify disease cohorts and perform genotype-phenotype association studies. The Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study, as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study, has genotyped more than 15,000 individuals of diverse genetic ancestry in BioVU, the Vanderbilt University Medical Center’s biorepository linked to a de-identified version of the EMR (EAGLE BioVU). Here we develop and deploy an algorithm utilizing data mining techniques to identify primary open-angle glaucoma (POAG) in African Americans from EAGLE BioVU for genetic association studies. The algorithm described here was designed using a combination of diagnostic codes, current procedural terminology billing codes, and free text searches to identify POAG status in situations where gold-standard digital photography cannot be accessed. The case algorithm identified 267 potential POAG subjects but underperformed after manual review with a positive predictive value of 51.6% and an accuracy of 76.3%. The control algorithm identified controls with a negative predictive value of 98.3%. Although the case algorithm requires more downstream manual review for use in large-scale studies, it provides a basis by which to extract a specific clinical subtype of glaucoma from EMRs in the absence of digital photographs.

Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study.

BackgroundSeveral regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.MethodsWe evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.ResultsWe observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4).ConclusionsWe provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

Abstract 56: Fine-Mapping of Metabochip Lipid Regions in Global Populations Identifies Signals Unique to Hispanic Descent Populations and Refines Previously Identified Lipid Loci

INTRODUCTION: Genome wide association studies (GWAS) have identified over 150 loci associated with lipids traits. The majority of these GWAS were performed in European Americans (EA); no large-scale studies exist for Hispanic descent populations. Additionally, in many cases, the genetic architecture of these trait-influencing loci remains largely unknown. To address these gaps in knowledge, we performed one of the most ethnically diverse fine-mapping genetic studies on HDL-C, LDL-C, and triglycerides (TG) to-date. HYPOTHESIS: Here we aimed to identify variants with the strongest association at each locus, detect population-specific signals, and refine previously identified EA GWAS loci. METHODS: We used Metabochip data from African American (AA, ~21,000), Hispanic American (HA, ~20,000), Asian (AS, ~2,000), and Native American (NA, ~550) participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study. We applied multiple linear regression models and assumed an additive mode of inheritance to test for association between genotypes and HDL-C, LDL-C, or log-transformed TG levels; lipid levels were corrected for lipid-lowering medication use. Model covariates included age, sex, and principal components of ancestry. We first conducted a meta-analysis within each ethnic group separately and then performed a combined trans-ethnic fixed effects meta-analysis. Significance was defined as p &lt; 1 x 10 -6 ; equivalent to 0.05/ the mean number of variants at each Metabochip lipid locus. RESULTS: For HDL-C, 19 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 5 of these loci, APOB, LIPC, STARD3, LIPG, and APOC1, have not been reported in EA. We identified a signal unique to HA at APOA5. In addition, we refined the set of candidate functional variants at PPP1R3B, LPL, and PLTP. For LDL-C, 16 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 5 of these loci, PCSK9, APOB, APOA5, CLIP2, and APOC1, have not been reported in EA. We identified a signal unique to HA at SLC22A1. In addition, we refined the set of candidate functional variants at TIMD4 and LDLR. For TG, 15 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 3 of these loci, APOB, APOA5, and LIPC, have not been reported in EA. In addition, we refined the set of candidate functional variants at ANGPTL3, MLXIPL, PPP1R3B, and LPL. CONCLUSIONS: By taking advantage of the genetic architecture of ethnically diverse populations, we identified novel lipid-influencing variants in HA and refined the set of candidate functional variants at GWAS lipid loci. Anticipated conditional analyses will provide further insight into secondary and ethnic-specific signals. Our results can guide the creation of more informed risk models, which can then be used for targeted prevention efforts, especially for underrepresented populations.

Leveraging Epidemiologic and Clinical Collections for Genomic Studies of Complex Traits

Background/Aims: Present-day limited resources demand DNA and phenotyping alternatives to the traditional prospective population-based epidemiologic collections. Methods: To accelerate genomic discovery with an emphasis on diverse populations, we - as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study - accessed all non-European American samples (n = 15,863) available in BioVU, the Vanderbilt University biorepository linked to de-identified electronic medical records, for genomic studies as part of the larger Population Architecture using Genomics and Epidemiology (PAGE) I study. Given previous studies have cautioned against the secondary use of clinically collected data compared with epidemiologically collected data, we present here a characterization of EAGLE BioVU, including the billing and diagnostic (ICD-9) code distributions for adult and pediatric patients as well as comparisons made for select health metrics (body mass index, glucose, HbA1c, HDL-C, LDL-C, and triglycerides) with the population-based National Health and Nutrition Examination Surveys (NHANES) linked to DNA samples (NHANES III, n = 7,159; NHANES 1999-2002, n = 7,839). Results: Overall, the distributions of billing and diagnostic codes suggest this clinical sample is a mixture of healthy and sick patients like that expected for a contemporary American population. Conclusion: Little bias is observed among health metrics, suggesting this clinical collection is suitable for genomic studies along with traditional epidemiologic cohorts.

Association of cancer susceptibility variants with risk of multiple primary cancers: The population architecture using genomics and epidemiology study.

Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Our study has identified rs578776 and rs11249433 as risk variants for IMPC. These findings may help to identify genetic regions associated with IMPC risk.

Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.

QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study.

Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci. Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study. Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing. While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.