Thomas J Hoffmann

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

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Publications (47)221.84 Total impact

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    ABSTRACT: We report a genome-wide association study (GWAS) of cutaneous squamous cell carcinoma (SCC) conducted among non-Hispanic white (NHW) members of the Kaiser Permanente Northern California (KPNC) health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5600 controls). Combined analysis of screening and replication phases identified ten loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5x10-8. Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate SCC risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated SCC risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited SCC susceptibility.
    Preview · Article · Jan 2016 · Journal of Investigative Dermatology
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    ABSTRACT: Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.European Journal of Human Genetics advance online publication, 6 January 2016; doi:10.1038/ejhg.2015.247.
    No preview · Article · Jan 2016 · European journal of human genetics: EJHG
  • Thomas J. Hoffmann · John S. Witte
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    ABSTRACT: Rare genetic variants may be responsible for a significant amount of the uncharacterized genetic risk underlying many diseases. An efficient approach to characterizing the disease burden of rare variants may be to impute them into existing large datasets. It is well known that the ability to impute a rare variant is dependent both on the array choice and number of individuals in the reference panel carrying that variant, although it is still unclear exactly how well imputation will work for rare variants. Here, we review the additional challenges that arise when imputing rare variants, looking at studies that have been able to impute rare variants, methods behind merging reference panels, approaches for imputing rare variants, and methods for analyzing rare variants. There have been an increasing number of success stories with regard to imputing rare variants, using different strategies such as merging reference panels.The number of sequenced individuals available for use as reference panels is increasing greatly, allowing us to better impute rarer variation.Tests that combine a group of similar rare variants (e.g., in a gene) initially intended for sequence data are being applied to imputed data, as it also begins to capture rarer variation.
    No preview · Article · Oct 2015 · Trends in Genetics
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    ABSTRACT: We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability. The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel. The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ε4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ε2 allele. These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits.
    No preview · Article · Jul 2015 · Investigative ophthalmology & visual science
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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.
    No preview · Article · Jun 2015 · Genetics
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    ABSTRACT: The Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis. Copyright © 2015, The Genetics Society of America.
    Full-text · Article · Jun 2015 · Genetics
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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.
    No preview · Article · Jun 2015 · Genetics
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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.
    No preview · Article · Jun 2015 · Cancer Discovery
  • 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.
    No preview · Article · May 2015 · Social Cognitive and Affective Neuroscience
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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.
    No preview · Article · May 2015 · Birth Defects Research Part A Clinical and Molecular Teratology
  • Victor Virlogeux · Rebecca E Graff · Thomas J Hoffmann · John S Witte
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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.
    No preview · Article · Mar 2015 · Cancer Epidemiology Biomarkers & Prevention
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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.
    Full-text · Article · Feb 2015 · Clinical Pharmacology &#38 Therapeutics
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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 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 Kaiser 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. 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 associated with an increase in risk for the fourteen other most common cancers considered collectively (p = 5.8×10−4) and more so in cases diagnosed with multiple cancer types, both those including and not including prostate cancer, strongly suggesting pleiotropic effects.
    Full-text · Article · Jan 2015 · PLoS Genetics
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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.
    Full-text · Article · Oct 2014 · PLoS Genetics
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    Preview · Article · Oct 2014 · American Journal of Medical Genetics Part A
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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.
    No preview · Article · Jul 2014 · Human Molecular Genetics
  • 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.
    No preview · Article · Jul 2014 · Brain and Cognition
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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 3.0% 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.
    No preview · Article · Jun 2014 · American Journal of Psychiatry
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    ABSTRACT: Importance Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD).Objective To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of ASD.Design, Setting, and Participants Individuals with ASD born from January 1, 1990, through December 31, 2003, were identified in the California Department of Developmental Services records, which were then linked to state birth certificates to identify full sibs and half-sibs and to obtain information on birth order and demographics. A total of 19 710 case families in which the first birth occurred within the study period was identified. These families included 39 361 individuals (sibs and half-sibs). Control individuals were randomly sampled from birth certificates and matched 2:1 to cases by sex, birth year, and maternal age, self-reported race/ethnicity, and county of birth after removal of children receiving services from the California Department of Developmental Services. Using similar linkage methods as for case families, 36 215 pure control families (including 75 724 total individuals) were identified that had no individuals with an ASD diagnosis.Exposures History of affected children.Main Outcomes and Measures Stoppage was investigated by comparing the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child using a survival analysis framework for time to next birth and adjusting for demographic variables.Results For the first few years after the birth of a child with ASD, the parents’ reproductive behavior was similar to that of control parents. However, birth rates differed in subsequent years; overall, families whose first child had ASD had a second child at a rate of 0.668 (95% CI, 0.635-0.701) that of control families, adjusted for birth year, birth weight, maternal age, and self-reported maternal race/ethnicity. Results were similar when a later-born child was the first affected child in the family. Reproductive curtailment was slightly stronger among women who changed partners (relative rate for second-born children, 0.553 [95% CI, 0.498-0.614]).Conclusions and Relevance These results provide the first quantitative assessment and convincing statistical evidence of reproductive stoppage related to ASD. These findings have implications for recurrence risk estimation and genetic counseling.
    No preview · Article · Jun 2014 · JAMA Psychiatry
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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.
    Full-text · Article · Jun 2014 · Genes Brain and Behavior

Publication Stats

447 Citations
221.84 Total Impact Points

Institutions

  • 2010-2015
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, California, United States
  • 2009-2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States