Thomas J Hoffmann

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

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Publications (41)190.12 Total impact

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    ABSTRACT: Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into 7 major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. PC and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed considering only non-adjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3,741 genetically-identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2,018 genetically-identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to inter-marriage. The parent-child pairs revealed a trend towards increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories, creates interesting challenges and future opportunities for genetic epidemiologic studies. Copyright © 2015, The Genetics Society of America.
    Genetics 06/2015; DOI:10.1534/genetics.115.178616 · 4.87 Impact Factor
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    ABSTRACT: The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California, San Francisco, undertook genome-wide genotyping of over 100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated over 70 billion genotypes, represents the first large scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 out of 109,837 samples assayed (93.8%), with a range of 92.1% to 95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1% to 99.4% across the four arrays, the variation mostly depending on how many SNPs were included as single copy versus double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions. Copyright © 2015, The Genetics Society of America.
    Genetics 06/2015; DOI:10.1534/genetics.115.178905 · 4.87 Impact Factor
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    ABSTRACT: A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously-identified locus 6q25.3 that replicated in PEGASUS (N=7,539) and MEC (N=4,679) (p=1.0x10(-19), OR=1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (p=1.3x10(-23)) and SLC22A3 (p=3.2x10(-52)). At the known 19q13.33 locus rs2659124 (p=1.3x10(-13), OR=1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (p<1.0x10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic Whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained ~7.6% of disease heritability. The entire GWAS array explained ~33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (p=0.004). Copyright © 2015, American Association for Cancer Research.
    Cancer Discovery 06/2015; DOI:10.1158/2159-8290.CD-15-0315 · 15.93 Impact Factor
  • Mark Wade, Thomas J Hoffmann, Jennifer M Jenkins
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    ABSTRACT: Theory of mind (ToM) is the ability to interpret and understand human behaviour by representing the mental states of others. Like many human capacities, ToM is thought to develop through both complex biological and socialization mechanisms. However, no study has examined the joint effect of genetic and environmental influences on ToM. The current study examined how variability in the oxytocin receptor gene (OXTR) and parenting behaviour - two widely studied factors in ToM development - interacted to predict ToM in preschool-aged children. Participants were 301 children who were part of an ongoing longitudinal birth cohort study. ToM was assessed at age 4.5 using a previously validated scale. Parenting was assessed through observations of mothers' cognitively sensitive behaviours. Using a family-based association design, it was suggestive that a particular variant (rs11131149) interacted with maternal cognitive sensitivity on children's ToM (p = .019). More copies of the major allele were associated with higher ToM as a function of increasing cognitive sensitivity. A sizeable 26% of the variability in ToM was accounted for by this interaction. This study provides the first empirical evidence of gene-environment interactions on ToM, supporting the notion that genetic factors may be modulated by potent environmental influences early in development. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
    Social Cognitive and Affective Neuroscience 05/2015; DOI:10.1093/scan/nsv064 · 5.88 Impact Factor
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    ABSTRACT: Background The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene–environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads.Methods In this study, we discuss important considerations in the collection of genetic data and environmental exposures.ResultsWe will also present several population- and family-based approaches that can be applied to data from the NBDPS including case–control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages.ConclusionA range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results. Birth Defects Research (Part A), 2015. © 2015 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 05/2015; DOI:10.1002/bdra.23382 · 2.21 Impact Factor
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    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; 24(6). DOI:10.1158/1055-9965.EPI-14-1372 · 4.32 Impact Factor
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    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; 97(5). DOI:10.1002/cpt.89 · 7.39 Impact Factor
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    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
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    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.
    PLoS Genetics 10/2014; 10(10). 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 · 2.05 Impact Factor
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    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
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    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
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    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
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    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
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    Mark Wade, Thomas J Hoffmann, Karen Wigg, Jennifer M Jenkins
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    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
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    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 · 2.05 Impact Factor
  • Mark Wade, Thomas J. Hoffmann, Jennifer M. Jenkins
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    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. · 2.68 Impact Factor
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    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
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    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
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    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

Publication Stats

286 Citations
190.12 Total Impact Points

Institutions

  • 2010–2015
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, California, United States
  • 2013
    • Stanford Medicine
      • Division of Cardiovascular Medicine
      Stanford, CA, United States
  • 2012
    • University of Washington Seattle
      • Department of Biostatistics
      Seattle, WA, United States
  • 2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007–2010
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States