Thomas J Hoffmann

University of California, San Francisco, San Francisco, California, United States

Are you Thomas J Hoffmann?

Claim your profile

Publications (36)156.97 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer incidence and mortality rates vary across populations, with African-American men exhibiting the highest rates. To date, genome wide association studies have identified 104 single nucleotide polymorphisms (SNPs) independently associated with prostate cancer in men of European ancestry. We investigated whether the ability to replicate findings for these 104 SNPs in African, Asian, and Latino populations depends on variation in risk allele frequencies (RAF), strength of associations, and/or patterns of linkage disequilibrium (LD) at the associated loci. We extracted estimates of effect and replication efforts from the literature, and determined RAF and linkage disequilibrium information across the populations from the 1000 Genomes project. Risk variants were largely replicated across populations. Relative to Europeans, 83% had smaller effect sizes among African-Americans and 73% demonstrated smaller effect sizes among Latinos. Among Asians, however, 56% showed larger effect sizes than among Europeans. The largest difference in risk allele frequencies was observed between European and African ancestry populations, but this difference did not impact our ability to replicate. The extent of linkage disequilibrium within 250kb of risk loci in Asian ancestry populations was suggestively lower for variants that did not replicate (p-value = 0.013). Despite substantial overlap in prostate cancer risk SNPs across populations, the variation in prostate cancer incidence between different populations may still in part reflect unique underlying genetic architectures. Studying different ancestral populations is crucial for deciphering the genetic basis of this common but complex disease. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 03/2015; DOI:10.1158/1055-9965.EPI-14-1372 · 4.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The first-line treatment of hyperuricemia, which causes gout, is allopurinol. Allopurinol response is highly variable with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol related SUA reduction, first in the largest ethnic group, non-Hispanic White (NHW) subjects, and then in a stratified trans-ethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (p=2x10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (p=3x10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
    Clinical Pharmacology &#38 Therapeutics 02/2015; DOI:10.1002/cpt.89 · 6.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that-by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers-we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men's Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37-0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10-12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin's lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).
    PLoS Genetics 01/2015; 11(1):e1004930. DOI:10.1371/journal.pgen.1004930 · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements. Citation: Smith RP, Eckalbar WL, Morrissey KM, Luizon MR, Hoffmann TJ, et al. (2014) Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements. PLoS Genet 10(10): e1004648. doi:10.1371/journal.pgen.1004648, ZD, YL, TCS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: KMG is a co-founder of Apricity Therapeutics, Inc, a company which focuses on membrane transporters in drug discovery and development. NDT and SFA are co-founders of SwitchGear Genomics.
    PLoS Genetics 10/2014; DOI:10.1371/journal.pgen.1004648 · 8.52 Impact Factor
  • American Journal of Medical Genetics Part A 10/2014; 164(10). DOI:10.1002/ajmg.a.36659 · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a genome-wide association study (GWAS) and admixture analysis of glaucoma in 12,008 African American and Hispanic women (age 50-79 years) from the Women's Health Initiative (WHI). Although GWAS of glaucoma have been conducted on several populations, this is the first to look at glaucoma in individuals of African American and Hispanic race/ethnicity. Prevalent and incident glaucoma was determined by self-report from study questionnaires administered at baseline (1993-1998) and annually through 2005. For African Americans, there was a total of 658 prevalent cases, 1,062 incident cases, and 6,067 individuals who never progressed to glaucoma. For our replication cohort, we used the WHI Hispanics, including 153 prevalent cases, 336 incident cases, and 2,685 non-cases. We found an association of African ancestry with glaucoma incidence in African Americans (hazards ratio 1.62, 95% CI 1.023 to 2.56, p=.038) and in Hispanics (hazards ratio 3.21, 95% CI 1.32 to 7.80, p=.011). Although we found that no previously identified glaucoma SNPs replicated in either the WHI African Americans or Hispanics, a risk score combining all previously reported hits was significant in African American prevalent cases (p=.0046), and was in the expected direction in the incident cases, as well as in the Hispanic incident cases. Additionally, after imputing to 1000 Genomes, two less common independent SNPs were suggestive in African Americans, but had too low of an allele frequency in Hispanics to test for replication. These results suggest the possibility of a distinct genetic architecture underlying glaucoma in individuals of African ancestry.
    Human Molecular Genetics 07/2014; DOI:10.1093/hmg/ddu364 · 6.68 Impact Factor
  • Mark Wade, Thomas J Hoffmann, Jennifer M Jenkins
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence implicates the arginine vasopressin (AVP) system in complex neuropsychological disorders which are characterized by deficits in executive functioning (EF). Despite the genetic contribution to EF, little is currently known about its molecular genetic basis. Drawing on research from social neuroscience and the role of related physiological systems in psychopathology, the current study hypothesized that variability in the AVP receptor 1a gene (AVPR1A) would be associated with EF in an epidemiological sample of 323 normally developing preschool-aged children. Using a family-based association design, the current study found that variability in the rs7298346 marker, located in the 5'-flanking region, was significantly related to a composite measure of EF in 4-year-old children after controlling for a variety of covariates and children's theory of mind. The converse association between AVPR1A and theory of mind (after controlling for EF) was not significant, suggesting a level of specificity in this relationship. The results are discussed in terms of the difficulties faced by genetic association studies in teasing apart the behavioral phenotypes that characterize complex psychological diseases and the involvement of multiple physiological systems in human behavior.
    Brain and Cognition 07/2014; 90C:116-123. DOI:10.1016/j.bandc.2014.06.002 · 2.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth. Method: The authors linked California Department of Developmental Services records with state birth certificates to identify all siblings and half siblings of individuals affected with ASD born between 1990 and 2003. A total of 6,616 full siblings, 644 maternal half siblings, and 299 paternal half siblings born after ASD index cases were used to calculate recurrence risks. Control families, identified through matching to cases, were included for comparison (a total of 29,384 siblings). Results: The overall sibling recurrence risk was 10.1%, compared with a prevalence of 0.52% in siblings of controls. The recurrence risk in second-born children was higher (11.5%) than in later-born siblings (7.3%); a similar pattern was observed for maternal half siblings (6.5% for second-born compared with 10% for later-born siblings; 4.8% overall). The recurrence risk was significantly higher for siblings who immediately followed the index case in birth order compared with those later in birth order. The recurrence risk for paternal half siblings (2.3%) was half the overall recurrence risk for maternal half siblings but was similar to that for later-born maternal half siblings. An exponential effect of short interbirth interval was observed, with the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more. An identical phenomenon was observed in maternal half siblings. Conclusions: The results support genetic susceptibility in the familial recurrence of ASD along with factors related to timing of birth.
    American Journal of Psychiatry 06/2014; 171(11). DOI:10.1176/appi.ajp.2014.13101359 · 13.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD).
    JAMA Psychiatry 06/2014; 71(8). DOI:10.1001/jamapsychiatry.2014.420 · 12.01 Impact Factor
  • Mark Wade, Thomas J Hoffmann, Karen Wigg, Jennifer M Jenkins
    [Show abstract] [Hide abstract]
    ABSTRACT: At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation, and self-recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social-cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, the current study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socioemotional functioning. At 18 months, social cognition was measured using previously validated and developmentally-sensitive tasks assessing children's joint attention, empathy, cooperation, and self-recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897, and rs237899. A family-based association design was used to control for population admixture and stratification, and additional non-genomic covariates were controlled. Results showed that that variability in rs11131149 was significantly associated with social cognition (p = .009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149-rs2254298 was also associated with social cognition (p = .020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.
    Genes Brain and Behavior 06/2014; 13(7). DOI:10.1111/gbb.12148 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Maternal smoking during pregnancy is one proposed risk factor for gastroschisis, but reported associations have been modest, suggesting that differences in genetic susceptibility might play a role. We included 108 non-Hispanic white and 62 Hispanic families who had infants with gastroschisis, and 1,147 non-Hispanic white and 337 Hispanic families who had liveborn infants with no major structural birth defects (controls) in these analyses. DNA was extracted from buccal cells collected from infants and mothers, and information on periconceptional smoking history was obtained from maternal interviews, as part of the National Birth Defects Prevention Study. We analyzed five polymorphisms in three genes that code for enzymes involved in metabolism of some cigarette smoke constituents (CYP1A1, CYP1A2, and NAT2). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) independently for maternal smoking and maternal and infant gene variants, and to assess joint associations of maternal smoking and maternal or infant gene variants with gastroschisis. In analyses adjusted for maternal age at delivery and stratified by maternal race-ethnicity, we identified three suggestive associations among 30 potential associations with sufficient numbers to calculate ORs: CYP1A1*2A for non-Hispanic white mothers who smoked periconceptionally (aOR = 0.38, 95% CI 0.15–0.98), and NAT2*6 for Hispanic non-smoking mothers (aOR = 2.17, 95% CI 1.12–4.19) and their infants (aOR = 2.11, 95% CI 1.00–4.48). This analysis does not support the occurrence of effect modification between periconceptional maternal smoking and most of the xenobiotic metabolizing enzyme gene variants assessed. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36478 · 2.30 Impact Factor
  • Mark Wade, Thomas J. Hoffmann, Jennifer M. Jenkins
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence implicates the arginine vasopressin (AVP) system in complex neuropsychological disorders which are characterized by deficits in executive functioning (EF). Despite the genetic contribution to EF, little is currently known about its molecular genetic basis. Drawing on research from social neuroscience and the role of related physiological systems in psychopathology, the current study hypothesized that variability in the AVP receptor 1a gene (AVPR1A) would be associated with EF in an epidemiological sample of 323 normally developing preschool-aged children. Using a family-based association design, the current study found that variability in the rs7298346 marker, located in the 5′-flanking region, was significantly related to a composite measure of EF in 4-year-old children after controlling for a variety of covariates and children’s theory of mind. The converse association between AVPR1A and theory of mind (after controlling for EF) was not significant, suggesting a level of specificity in this relationship. The results are discussed in terms of the difficulties faced by genetic association studies in teasing apart the behavioral phenotypes that characterize complex psychological diseases and the involvement of multiple physiological systems in human behavior.
    Brain and Cognition 01/2014; 90:116–123. · 2.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Haploinsufficiency of the Single Minded homology 1 (SIM1) gene in humans and mice leads to severe obesity, suggesting that altered expression of SIM1, by way of regulatory elements such as enhancers, could predispose individuals to obesity. Here, we identified transcriptional enhancers that could regulate SIM1, using comparative genomics coupled with zebrafish and mouse transgenic enhancer assays. Due to the dual role of Sim1 in hypothalamic development and in adult energy homeostasis, the enhancer activity of these sequences was annotated from embryonic to adult age. Of the seventeen tested sequences, two (SCE2 and SCE8) were found to have brain enhancer activity in zebrafish. Both SCE2 and SCE8 also exhibited embryonic brain enhancer expression in mice, and time course analysis of SCE2 activity showed overlapping expression with Sim1 from embryonic to adult age, notably in the hypothalamus in adult mice. Using a deletion series, we identified the critical region in SCE2 that is needed for enhancer activity in the developing brain. Sequencing this region in obese and lean cohorts revealed a higher prevalence of SNPs that were unique to obese individuals, with one variant reducing developmental enhancer activity in zebrafish. In summary, we have characterized two brain enhancers in the SIM1 locus and identified a set of obesity-specific SNPs within one of them, which may predispose individuals to obesity.
    Human Molecular Genetics 11/2013; 23(7). DOI:10.1093/hmg/ddt559 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims Age-related macular degeneration (AMD) is the most common cause of vision loss in individuals over the age of 50 in the United States. Genetic factors explain a large portion of the risk of developing AMD, and genetic variants at the CFH, HTRA1/ARMS2, C2/CFB, and C3 gene loci have previously been associated with the disease. Methods We conducted a genome-wide association study (GWAS) of AMD in the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The GERA cohort includes 110,266 subjects with extensive electronic medical record information on eye examinations, diagnoses and treatment of vision disorders, and dense genome-wide genotype information on more than 675,000 genetic markers generated using Affymetrix Axiom arrays. The cohort is ethnically diverse, with 7.5% Asian, 7% Latino, 3.5% African American, and 81% non-Hispanic white subjects. We identified a total of 2,147 AMD cases (46 Asian, 125 Latino, 11 African American, and 1,965 non-Hispanic whites) and 37,521 controls (2,013 Asian, 3,201 Latino, 1,168 African American, and 31,139 non-Hispanic whites) for analysis. Analyses were conducted separately for each race/ethnicity group. Results In the largest group, non-Hispanic whites, we identified highly significant associations with variants in the CFH and HTRA1/ARMS2 gene regions, and genome-wide significant associations in the C2/CFB and C3 gene regions. Conclusions These results confirm those of previous studies and demonstrate the power of the GERA cohort for combining information from electronic medical records with extensive genotype data. This approach can be applied to additional vision disorder phenotypes, including response to treatment and disease progression.
    Clinical Medicine &amp Research 09/2013; 11(3):146-147. DOI:10.3121/cmr.2013.1176.b4-4
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims The Kaiser Permanente/UCSF Genetic Epidemiology Research Study on Adult Health and Aging (GERA) cohort includes 110,266 individuals with comprehensive longitudinal medical records along with genome-wide genotype data. As such, it provides an unprecedented opportunity to conduct a number of genome-wide association studies (GWAS) of psychiatric disorders. Post-traumatic stress disorder (PTSD) and panic disorder (PD) are prevalent, persistent, disabling and heritable anxiety disorders. Numerous candidate gene studies have been published with inconsistent findings. We conducted the GWAS of PTSD and the GWAS of panic disorder among non-Hispanic white GERA cohorts to detect the underlying heterogeneous genetic architecture. Methods We identified a total of 6177 combined ASD and PTSD cases in the GERA cohort, in which cases had two or more psychiatric diagnoses of ASD and/or PTSD; the GERA cohort supplied 63,613 controls. A total of 1483 subjects with two or more diagnoses of panic disorder and 75,379 controls were included in the GWAS of panic disorder. All the cases and controls were genotyped on the custom Affymetrix Axiom EUR arrays with 674,518 SNPs. Results In the GWAS of combined ASD and PTSD or the GWAS of PD, a suggestive association with ASD/PTSD was found with a SNP in an intergenic region on chromosome 10 near the ANKRD20A gene (OR = 1.11, P = 1.42×10-7), as well as neighboring SNPs. In the GWAS of PD, we replicated a SNP association (rs1873727) in intron 3 of TMEM132D which was reported in a recent GWAS of PD. Conclusions Our analysis did not yield conclusive associations with PTSD or PD. We replicated a candidate gene in TMEM132D in the PD analysis. This suggests that we can observe true association signals for these disorders, but additional cases are needed to detect modest effects. GWAS of psychiatric disorders remain challenging.
    Clinical Medicine &amp Research 09/2013; 11(3):149. DOI:10.3121/cmr.2013.1176.ps3-15
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF risk. The Women's Health Initiative (WHI) Observational Study (OS) followed up 93,676 women since the mid 1990s for various cardiovascular outcomes including AF. Multivariate Cox hazard regression analysis was used to measure the association between African American race and incident AF. A total of 8,119 African American women from the WHI randomized clinical trials and OS were genotyped on the Affymetrix Human SNP Array 6.0. Genome-wide ancestry and previously reported single nucleotide polymorphisms associated with AF in European cohorts were tested for association with AF using multivariate logistic regression analyses. Self-reported African American race was associated with lower rates of AF (hazard ratio 0.43, 95% CI 0.32-0.60) in the OS, independent of demographic and clinical risk factors. In the genotyped cohort, there were 558 women with AF. By contrast, genome-wide European ancestry was not associated with AF. None of the single nucleotide polymorphisms previously associated with AF in European populations, including rs2200733, were associated with AF in the WHI African American cohort. African American race is significantly and inversely correlated with AF in postmenopausal women. The etiology of this association remains unclear and may be related to unidentified environmental differences. Larger studies are necessary to identify genetic determinants of AF in African Americans.
    American heart journal 09/2013; 166(3):566-572.e1. DOI:10.1016/j.ahj.2013.05.024 · 4.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE:Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.METHODS:The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.RESULTS:Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.CONCLUSIONS:We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.
    PEDIATRICS 07/2013; 132(2). DOI:10.1542/peds.2013-0533 · 5.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.
    The American Journal of Human Genetics 05/2013; 92(6). DOI:10.1016/j.ajhg.2013.04.025 · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk. We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women's Health Initiative SNP Health Association Resource cohort of 3,642 self-identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1, and ADIPOR2. The genome-wide human SNP array 6.0 (909,622 SNPs) ( www.affymetrix.com ) was used. We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95 % CI 1.059-1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence. This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment.
    Breast Cancer Research and Treatment 04/2013; 139(2). DOI:10.1007/s10549-013-2546-6 · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with complex traits. However, the genetic heritability of most of these traits remains unexplained. To help guide future studies, we address the crucial question of whether future GWAS can detect new SNP associations and explain additional heritability given the new availability of larger GWAS SNP arrays, imputation, and reduced genotyping costs. We first describe the pairwise and imputation coverage of all SNPs in the human genome by commercially available GWAS SNP arrays, using the 1000 Genomes Project as a reference. Next, we describe the findings from 6 years of GWAS of 172 chronic diseases, calculating the power to detect each of them while taking array coverage and sample size into account. We then calculate the power to detect these SNP associations under different conditions using improved coverage and/or sample sizes. Finally, we estimate the percentages of SNP associations and heritability previously detected and detectable by future GWAS under each condition. Overall, we estimated that previous GWAS have detected less than one-fifth of all GWAS-detectable SNPs underlying chronic disease. Furthermore, increasing sample size has a much larger impact than increasing coverage on the potential of future GWAS to detect additional SNP-disease associations and heritability.
    Genetic Epidemiology 03/2013; DOI:10.1002/gepi.21724 · 2.95 Impact Factor

Publication Stats

259 Citations
156.97 Total Impact Points

Institutions

  • 2010–2015
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, California, United States
  • 2014
    • CSU Mentor
      Long Beach, California, United States
  • 2013
    • Institute of Human Genetics
      Amadavad, Gujarat, India
    • Stanford Medicine
      • Division of Cardiovascular Medicine
      Stanford, CA, United States
  • 2012
    • University of Washington Seattle
      • Department of Biostatistics
      Seattle, WA, United States
  • 2007–2010
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States