Thomas J Hoffmann

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

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Publications (28)106.02 Total impact

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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; · 7.69 Impact Factor
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    ABSTRACT: 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.
    The American journal of psychiatry. 06/2014;
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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; · 12.01 Impact Factor
  • American Journal of Medical Genetics Part A 06/2014; · 2.30 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 01/2014; · 2.30 Impact Factor
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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.
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    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. · 4.65 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.
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    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; · 4.47 Impact Factor
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    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; · 11.20 Impact Factor
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    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; · 4.47 Impact Factor
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    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; · 4.02 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to appropriately account for both pedigree and population structure can lead to spurious association. A number of methods have been proposed for identifying relatives in samples from homogeneous populations. A strong assumption of population homogeneity, however, is often untenable, and many GWASs include samples from structured populations. Here, we consider the problem of estimating relatedness in structured populations with admixed ancestry. We propose a method, REAP (relatedness estimation in admixed populations), for robust estimation of identity by descent (IBD)-sharing probabilities and kinship coefficients in admixed populations. REAP appropriately accounts for population structure and ancestry-related assortative mating by using individual-specific allele frequencies at SNPs that are calculated on the basis of ancestry derived from whole-genome analysis. In simulation studies with related individuals and admixture from highly divergent populations, we demonstrate that REAP gives accurate IBD-sharing probabilities and kinship coefficients. We apply REAP to the Mexican Americans in Los Angeles, California (MXL) population sample of release 3 of phase III of the International Haplotype Map Project; in this sample, we identify third- and fourth-degree relatives who have not previously been reported. We also apply REAP to the African American and Hispanic samples from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe) study, in which hundreds of pairs of cryptically related individuals have been identified.
    The American Journal of Human Genetics 06/2012; 91(1):122-38. · 11.20 Impact Factor
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    Rémi Kazma, Thomas J Hoffmann, John S Witte
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    ABSTRACT: Rare variants may help to explain some of the missing heritability of complex diseases. Technological advances in next-generation sequencing give us the opportunity to test this hypothesis. We propose two new methods (one for case-control studies and one for family-based studies) that combine aggregated rare variants and common variants located within a region through principal components analysis and allow for covariate adjustment. We analyzed 200 replicates consisting of 209 case subjects and 488 control subjects and compared the results to weight-based and step-up aggregation methods. The principal components and collapsing method showed an association between the gene FLT1 and the quantitative trait Q1 (P<10-30) in a fraction of the computation time of the other methods. The proposed family-based test has inconclusive results. The two methods provide a fast way to analyze simultaneously rare and common variants at the gene level while adjusting for covariates. However, further evaluation of the statistical efficiency of this approach is warranted.
    BMC proceedings 11/2011; 5 Suppl 9:S29.
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    ABSTRACT: Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.
    Genomics 08/2011; 98(6):422-30. · 3.01 Impact Factor
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    ABSTRACT: The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.
    Genomics 04/2011; 98(2):79-89. · 3.01 Impact Factor
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    ABSTRACT: It is useful to have robust gene-environment interaction tests that can utilize a variety of family structures in an efficient way. This article focuses on tests for gene-environment interaction in the presence of main genetic and environmental effects. The objective is to develop powerful tests that can combine trio data with parental genotypes and discordant sibships when parents' genotypes are missing. We first make a modest improvement on a method for discordant sibs (discordant on phenotype), but the approach does not allow one to use families when all offspring are affected, e.g., trios. We then make a modest improvement on a Mendelian transmission-based approach that is inefficient when discordant sibs are available, but can be applied to any nuclear family. Finally, we propose a hybrid approach that utilizes the most efficient method for a specific family type, then combines over families. We utilize this hybrid approach to analyze a chronic obstructive pulmonary disorder dataset to test for gene-environment interaction in the Serpine2 gene with smoking. The methods are freely available in the R package fbati.
    Biometrics 03/2011; 67(4):1260-70. · 1.41 Impact Factor
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    Kenneth S Kompass, Thomas J Hoffmann, John S Witte
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    ABSTRACT: With the advent of high throughput genomics and high-resolution imaging techniques, there is a growing necessity in biology and medicine for parallel computing, and with the low cost of computing, it is now cost-effective for even small labs or individuals to build their own personal computation cluster. Here we briefly describe how to use commodity hardware to build a low-cost, high-performance compute cluster, and provide an in-depth example and sample code for parallel execution of R jobs using MOSIX, a mature extension of the Linux kernel for parallel computing. A similar process can be used with other cluster platform software. As a statistical genetics example, we use our cluster to run a simulated eQTL experiment. Because eQTL is computationally intensive, and is conceptually easy to parallelize, like many statistics/genetics applications, parallel execution with MOSIX gives a linear speedup in analysis time with little additional effort. We have used MOSIX to run a wide variety of software programs in parallel with good results. The limitations and benefits of using MOSIX are discussed and compared to other platforms.
    Source Code for Biology and Medicine 03/2011; 6:4.
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    John S Witte, Thomas J Hoffmann
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    ABSTRACT: Genome-wide association studies (GWAS) have successfully detected and replicated associations with numerous diseases, including cancers of the prostate and breast. These findings are helping clarify the genomic basis of such diseases, but appear to explain little of disease heritability. This limitation might reflect the focus of conventional GWAS on a small set of the most statistically significant associations with disease. More information might be obtained by analyzing GWAS using a polygenic model, which allows for the possibility that thousands of genetic variants could impact disease. Furthermore, there may exist common polygenic effects between potentially related phenotypes (e.g., prostate and breast cancer). Here we present and apply a polygenic model to GWAS of prostate and breast cancer. Our results indicate that the polygenic model can explain an increasing--albeit low--amount of heritability for both of these cancers, even when excluding the most statistically significant associations. In addition, nonaggressive prostate cancer and breast cancer appear to share a common polygenic model, potentially reflecting a similar underlying biology. This supports the further development and application of polygenic models to genomic data.
    Omics: a journal of integrative biology 02/2011; 15(6):393-8. · 2.29 Impact Factor
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    Thomas J. Hoffmann
    Journal of statistical software 01/2011; 39(c01). · 4.91 Impact Factor

Publication Stats

185 Citations
106.02 Total Impact Points

Institutions

  • 2010–2014
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, California, United States
  • 2011–2013
    • CSU Mentor
      Long Beach, California, United States
  • 2012
    • University of Washington Seattle
      • Department of Biostatistics
      Seattle, WA, United States
  • 2007–2011
    • Harvard University
      • Department of Biostatistics
      Boston, MA, United States
  • 2007–2010
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States