Sebastian Zöllner
Research interests
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Interestsskilled nursing facility
Publications
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5.09Impact points
Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics.
Journal of clinical psychopharmacology. 04/2012; 32(2):261-5.
Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 12... [more] Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (χ = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (χ = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.
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4.93Impact points
FTEC: A Coalescent Simulator for Modeling Faster than Exponential Growth.
Bioinformatics (Oxford, England). 03/2012;
SUMMARY: Recent genetic studies as well as recorded history point to massive growth in human population sizes during the recent past. To model and understand this growth accurately we introduce FTEC, an easy to use coalescent simulation program capable of simulating haplotype samples drawn from a po... [more] SUMMARY: Recent genetic studies as well as recorded history point to massive growth in human population sizes during the recent past. To model and understand this growth accurately we introduce FTEC, an easy to use coalescent simulation program capable of simulating haplotype samples drawn from a population that has undergone faster than exponential growth. Samples drawn from a population that has undergone faster than exponential growth show an excess of very rare variation and more rapid LD decay when compared to samples drawn from a population that has maintained a constant size over time. AVAILABILITY: Source code for FTEC is freely available for download from the University of Michigan Center for Statistical Genetics Wiki at http://genome.sph.umich.edu/wiki/FTEC. CONTACT: mreppell@umich.edu, szoellne@umich.edu.
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15.05Impact points
Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.
Molecular psychiatry. 01/2012;
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susc... [more] We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.Molecular Psychiatry advance online publication, 3 January 2012; doi:10.1038/mp.2011.174.
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3.09Impact points
Next generation analytic tools for large scale genetic epidemiology studies of complex diseases.
Genetic epidemiology. 12/2011;
Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To iden... [more] Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To identify obstacles to future progress in genetic epidemiology research and provide recommendations to NIH for overcoming these barriers, the National Cancer Institute sponsored a workshop entitled "Next Generation Analytic Tools for Large-Scale Genetic Epidemiology Studies of Complex Diseases" on September 15-16, 2010. The goal of the workshop was to facilitate discussions on (1) statistical strategies and methods to efficiently identify genetic and environmental factors contributing to the risk of complex disease; and (2) how to develop, apply, and evaluate these strategies for the design, analysis, and interpretation of large-scale complex disease association studies in order to guide NIH in setting the future agenda in this area of research. The workshop was organized as a series of short presentations covering scientific (gene-gene and gene-environment interaction, complex phenotypes, and rare variants and next generation sequencing) and methodological (simulation modeling and computational resources and data management) topic areas. Specific needs to advance the field were identified during each session and are summarized. Genet. Epidemiol. © 2011 Wiley Periodicals, Inc.
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8.20Impact points
Wounds, functional disability, and indwelling devices are associated with cocolonization by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in southeast Michigan.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 12/2011; 53(12):1215-22.
Methicillin-resistant Staphylococcus aureus (MRSA) remains sensitive to vancomycin; when vancomycin-resistant S. aureus (VRSA) emerges, treatment becomes more complex. VRSA emergence is attributed to conjugative transfer of the vancomycin-resistance gene cluster from vancomycin-resistant enterococci... [more] Methicillin-resistant Staphylococcus aureus (MRSA) remains sensitive to vancomycin; when vancomycin-resistant S. aureus (VRSA) emerges, treatment becomes more complex. VRSA emergence is attributed to conjugative transfer of the vancomycin-resistance gene cluster from vancomycin-resistant enterococci (VRE) to MRSA. Because cocolonization with MRSA and VRE precedes VRSA development, this study investigates the epidemiology of cocolonization in skilled nursing facility (SNF) residents at high risk for MRSA or VRE colonization. A prospective observational study conducted at 15 SNFs in southeast Michigan. Overall, 178 residents (90 with indwelling urinary catheters and/or feeding tubes and 88 device-free) were cultured monthly for MRSA and VRE, and clinical data were recorded. The incidence of MRSA/VRE cocolonization among residents with indwelling devices was 6.5 per 100 resident-months; 5.2 (95% confidence interval [CI]: 1.49-18.1) times that among those without devices. MRSA/VRE cocolonization in the device group occurred most frequently in wounds (4.1 per 100 resident-months). In a logistic regression analysis limited to residents with devices, functional disability (rate ratio [RR], 1.3; 95% CI: 1.1-1.4) and wound presence (RR, 3.4; 95% CI: 1.4-8.6) were independent risk factors of cocolonization. In a population of SNF residents, individuals with indwelling devices who also had functional disability or wounds were at greatest risk of MRSA/VRE cocolonization. These individuals should be routinely monitored for the presence of VRSA colonization.
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34.28Impact points
Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
Nature genetics. 09/2011; 43(10):977-83.
We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and fou... [more] We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
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9.53Impact points
Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.
PLoS genetics. 06/2011; 7(6):e1002134.
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,4... [more] Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
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8.93Impact points
Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs).
Schizophrenia research. 04/2011; 130(1-3):20-6.
Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psycho... [more] Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psychopathology as well as cardioprotection. This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning. Schizophrenia subjects were screened for the metabolic syndrome along with physical activity, smoking, and variants related to folate pharmacogenetics in this cross-sectional analysis. Arteriole endothelial-dependent vasodilatation was measured using non-invasive peripheral arterial tonometry (RH-PAT, EndoPAT2000). A 24h dietary food recall was used to construct intake profiles using the Nutrition Data Systems for Research software (NDSR). We examined associations between AAP use and RH-PAT values, and the influence of N-3 FA dietary intake on this measure. Preliminary data are reported in 83 subjects with a mean age (±s.d.) of 45.89 (±11.49), 64% were Caucasian (n=53), 64% were male (n=53), and 77% were receiving AAP treatment (n=63). A significant positive relationship was found between RH-PAT values and N-3 FA intake (F=17.7(1,16), p=0.0007) in subjects not receiving AAPs. This relationship was lost in those treated with AAPs (F=0.25(1,43), p>0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between RH-PAT and N-3 FAs (p=0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants. AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. AAP use may necessitate a higher N-3 FA dose to regain these effects, but additional research is necessary to strengthen the preliminary findings. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk.
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5.50Impact points
Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs.
Bipolar disorders. 12/2010; 12(8):786-92.
Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for bipolar disorder (BP). We performed a detailed association analysis assessing the contribution of common genetic variation in this region to the risk of BP. We analyzed 2,756 single nucleo... [more] Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for bipolar disorder (BP). We performed a detailed association analysis assessing the contribution of common genetic variation in this region to the risk of BP. We analyzed 2,756 single nucleotide polymorphism (SNP) markers in the chromosome 8q24 region of 3,512 individuals from 737 families. In addition, we extended genotype imputation methods to family-based data and imputed 22,725 HapMap SNPs in the same region on 8q24. We applied a family-based method to test 15,552 high-quality genotyped or imputed SNPs for association with BP. Our association analysis identified the most significant marker (p=4.80 × 10(-5) ), near the gene encoding potassium voltage-gated channel KQT-like protein (KCNQ3). Other marginally significant markers were located near adenylate cyclase 8 (ADCY8) and ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3GAL1). We developed an approach to apply MACH imputation to family-based data, which can increase the power to detect association signals. Our association results showed suggestive evidence of association of BP with loci near KCNQ3, ADCY8, and ST3GAL1. Consistent with genes identified by genome-wide association studies for BP, our results suggest the involvement of ion channelopathy in BP pathogenesis. However, common variants are insufficient to explain linkage findings in 8q24; other genetic variation should be explored.
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12.30Impact points
Extending rare-variant testing strategies: analysis of noncoding sequence and imputed genotypes.
American journal of human genetics. 11/2010; 87(5):604-17.
Next Generation Sequencing Technology has revolutionized our ability to study the contribution of rare genetic variation to heritable traits. However, existing single-marker association tests are underpowered for detecting rare risk variants. A more powerful approach involves pooling methods that co... [more] Next Generation Sequencing Technology has revolutionized our ability to study the contribution of rare genetic variation to heritable traits. However, existing single-marker association tests are underpowered for detecting rare risk variants. A more powerful approach involves pooling methods that combine multiple rare variants from the same gene into a single test statistic. Proposed pooling methods can be limited because they generally assume high-quality genotypes derived from deep-coverage sequencing, which may not be available. In this paper, we consider an intuitive and computationally efficient pooling statistic, the cumulative minor-allele test (CMAT). We assess the performance of the CMAT and other pooling methods on datasets simulated with population genetic models to contain realistic levels of neutral variation. We consider study designs ranging from exon-only to whole-gene analyses that contain noncoding variants. For all study designs, the CMAT achieves power comparable to that of previously proposed methods. We then extend the CMAT to probabilistic genotypes and describe application to low-coverage sequencing and imputation data. We show that augmenting sequence data with imputed samples is a practical method for increasing the power of rare-variant studies. We also provide a method of controlling for confounding variables such as population stratification. Finally, we demonstrate that our method makes it possible to use external imputation templates to analyze rare variants imputed into existing GWAS datasets. As proof of principle, we performed a CMAT analysis of more than 8 million SNPs that we imputed into the GAIN psoriasis dataset by using haplotypes from the 1000 Genomes Project.
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Using GWAS Data to Identify Copy Number Variants Contributing to Common Complex Diseases
10/2010;
Copy number variants (CNVs) account for more polymorphic base pairs in the human genome than do single nucleotide polymorphisms (SNPs). CNVs encompass genes as well as noncoding DNA, making these polymorphisms good candidates for functional variation. Consequently, most modern genome-wide associatio... [more] Copy number variants (CNVs) account for more polymorphic base pairs in the human genome than do single nucleotide polymorphisms (SNPs). CNVs encompass genes as well as noncoding DNA, making these polymorphisms good candidates for functional variation. Consequently, most modern genome-wide association studies test CNVs along with SNPs, after inferring copy number status from the data generated by high-throughput genotyping platforms. Here we give an overview of CNV genomics in humans, highlighting patterns that inform methods for identifying CNVs. We describe how genotyping signals are used to identify CNVs and provide an overview of existing statistical models and methods used to infer location and carrier status from such data, especially the most commonly used methods exploring hybridization intensity. We compare the power of such methods with the alternative method of using tag SNPs to identify CNV carriers. As such methods are only powerful when applied to common CNVs, we describe two alternative approaches that can be informative for identifying rare CNVs contributing to disease risk. We focus particularly on methods identifying de novo CNVs and show that such methods can be more powerful than case-control designs. Finally we present some recommendations for identifying CNVs contributing to common complex disorders. Comment: Published in at http://dx.doi.org/10.1214/09-STS304 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org)
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15.05Impact points
Genome-wide association study of bipolar disorder in European American and African American individuals.
Molecular psychiatry. 07/2009;
To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=... [more] To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.Molecular Psychiatry advance online publication, 2 June 2009; doi:10.1038/mp.2009.43.
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34.28Impact points
Segmental copy number variation shapes tissue transcriptomes.
Nature genetics. 05/2009; 41(4):424-9.
Copy number variation (CNV) is a key source of genetic diversity, but a comprehensive understanding of its phenotypic effect is only beginning to emerge. We have generated a CNV map in wild mice and classical inbred strains. Genome-wide expression data from six major organs show not only that expres... [more] Copy number variation (CNV) is a key source of genetic diversity, but a comprehensive understanding of its phenotypic effect is only beginning to emerge. We have generated a CNV map in wild mice and classical inbred strains. Genome-wide expression data from six major organs show not only that expression of genes within CNVs tend to correlate with copy number changes, but also that CNVs influence the expression of genes in their vicinity, an effect that extends up to half a megabase. Genes within CNVs show lower expression and more specific spatial expression patterns than genes mapping elsewhere. Our analyses reveal differential constraint on copy number changes of genes expressed in different tissues. Dosage alterations of brain-expressed genes are less frequent than those of other genes and are buffered by tighter transcriptional regulation. Our study provides initial evidence that CNVs shape tissue transcriptomes on a global scale.
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3.48Impact points
Suggestive linkage at 9p22 in bipolar disorder weighted by alcohol abuse.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 04/2009;
Bipolar disorder (BP) is a highly heritable disorder, however attempts to map genetic risk factors are challenging. One possible reason for these difficulties is the genetic heterogeneity of BP. Hence, focusing on clinically homogeneous families to create a genetically more homogeneous sample may in... [more] Bipolar disorder (BP) is a highly heritable disorder, however attempts to map genetic risk factors are challenging. One possible reason for these difficulties is the genetic heterogeneity of BP. Hence, focusing on clinically homogeneous families to create a genetically more homogeneous sample may increase the power of finding a specific variant. Alcohol abuse (AA) and alcohol dependence (AD) are familial in BP families, and these families may carry a specific risk variant for BP. We tested this hypothesis by performing a genome-wide linkage scan in 638 pedigrees (1,835 individuals) from the National Institute of Mental Health Genetics Initiative for BP, weighting the evidence for linkage according to the family's frequency of AA or AD. Using AA weighting, we identified a linkage region on 9p22.2 with an NPL score of 3.23. The region had previously been identified in a meta-analysis of linkage in bipolar disorder. We used permutation analysis to assess if weighting by AA increased the linkage signal more than expected by chance and observed a significant P-value (P = 0.048). Therefore, the genetic risk factor for BP on 9p22.2 has an increased effect in families with high levels of AA. In summary, we present an example of using covariates such as AA and AD to define subtypes of BP, demonstrate how using such subtypes can improve the power of a linkage scan, and demonstrate statistical approaches to validate the suggested interaction. (c) 2009 Wiley-Liss, Inc.
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15.05Impact points
Singleton deletions throughout the genome increase risk of bipolar disorder.
Molecular psychiatry. 01/2009;
An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetri... [more] An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania </=18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.Molecular Psychiatry advance online publication, 30 December 2008; doi:10.1038/mp.2008.144.
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3.09Impact points
Bayesian EM algorithm for scoring polymorphic deletions from SNP data and application to a common CNV on 8q24.
Genetic epidemiology. 01/2009;
Copy number variations (CNVs) in the human genome provide exciting candidates for functional polymorphisms. Hence, we now assess association between CNV carrier status and diseases status by evaluating the signal intensity of SNP genotyping assays. Here, we present a novel statistical method designe... [more] Copy number variations (CNVs) in the human genome provide exciting candidates for functional polymorphisms. Hence, we now assess association between CNV carrier status and diseases status by evaluating the signal intensity of SNP genotyping assays. Here, we present a novel statistical method designed to perform such inference and apply this method to a known CNV in a bipolar disorder linkage region. Using Bayesian computations we calculate the posterior probability for carrier status of a CNV in each individual of a sample by jointly analyzing genotype information and hybridization intensity. We model the signal intensity as a mixture of normal distributions, allowing for locus-specific and allele-specific distributions. Using an expectation maximization algorithm we estimate the parameters of these distributions and use these estimates for inferring carrier status of each individual and for the boundaries of the CNV. We applied the method to a sample of 3,512 individuals to a previously described common deletion on 8q24, a region consistently showing linkage to bipolar disorder, and unambiguously inferred 172 heterozygous and 1 homozygous deletion carrier. We observed no significant association between bipolar disorder and carrier status. We carefully assessed the validity of the inferred carrier status and observed no indication of errors. Furthermore, the algorithm precisely identifies the boundaries of the CNV. Finally, we assessed the power of this algorithm to detect shorter CNVs by sub-sampling from the SNPs covered by this deletion, demonstrating that our EM algorithm produces precise estimates of carrier status. Genet. Epidemiol. 2008. Published 2008 Wiley-Liss, Inc.
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34.28Impact points
Mouse segmental duplication and copy number variation.
Nature genetics. 08/2008; 40(7):909-14.
Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. However, the architecture of mouse and human genomes differs ... [more] Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. However, the architecture of mouse and human genomes differs markedly: most mouse duplications are organized into discrete clusters of tandem duplications that show depletion of genes and transcripts and enrichment of long interspersed nuclear element (LINE) and long terminal repeat (LTR) retroposons. We assessed copy number variation of the C57BL/6J duplicated regions within 15 mouse strains previously used for genetic association studies, sequencing and the Mouse Phenome Project. We determined that over 60% of these base pairs are polymorphic among the strains (on average, there was 20 Mb of copy-number-variable DNA between different mouse strains). Our data suggest that different mouse strains show comparable, if not greater, copy number polymorphism when compared to human; however, such variation is more locally restricted. We show large and complex patterns of interstrain copy number variation restricted to large gene families associated with spermatogenesis, pregnancy, viviparity, pheromone signaling and immune response.
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27.82Impact points
Psychiatric genetics: progress amid controversy.
Nature reviews. Genetics. 08/2008; 9(7):527-40.
Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotyp... [more] Several psychiatric disorders--such as bipolar disorder, schizophrenia and autism--are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case-control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.
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3.48Impact points
Family-based SNP association study on 8q24 in bipolar disorder.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 07/2008; 147B(5):612-8.
Previous linkage studies have identified chromosome 8q24 as a promising positional candidate region to search for bipolar disorder (BP) susceptibility genes. We, therefore, sought to identify BP susceptibility genes on chromosome 8q24 using a family-based association study of a dense panel of SNPs s... [more] Previous linkage studies have identified chromosome 8q24 as a promising positional candidate region to search for bipolar disorder (BP) susceptibility genes. We, therefore, sought to identify BP susceptibility genes on chromosome 8q24 using a family-based association study of a dense panel of SNPs selected to tag the known common variation across the region of interest. A total of 1,458 SNPs across 16 Mb of 8q24 were examined in 3,512 subjects, 1,954 of whom were affected with BP, from 737 multiplex families. Single-locus tests were carried out with FBAT and Geno-PDT, and multi-locus test were carried out with HBAT and multi-locus Geno-PDT. None of the SNPs were associated with BP in the single-locus tests at a level that exceeded our threshold for study-wide significance (P < 3.00 x 10(-5)). However, there was consistent evidence at our threshold for the suggestive level (P < 7.00 x 10(-4)) from both the single locus and multi-locus tests of associations with SNPs in the genes ADCY8, ST3GAL1, and NSE2. Multi-locus analyses suggested joint effects between ADCY8 and ST3GAL1 (P = 3.00 x 10(-4)), with at least one copy of the "high risk" allele required at both genes for association with BP, consistent with a jointly dominant-dominant model of action. These findings with ADCY8 and ST3GAL1 warrant further investigation in order to confirm the observed associations and their functional significance for BP susceptibility.
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4.93Impact points
GENOME: a rapid coalescent-based whole genome simulator.
Bioinformatics (Oxford, England). 07/2007; 23(12):1565-7.
SUMMARY: GENOME proposes a rapid coalescent-based approach to simulate whole genome data. In addition to features of standard coalescent simulators, the program allows for recombination rates to vary along the genome and for flexible population histories. Within small regions, we have evaluated samp... [more] SUMMARY: GENOME proposes a rapid coalescent-based approach to simulate whole genome data. In addition to features of standard coalescent simulators, the program allows for recombination rates to vary along the genome and for flexible population histories. Within small regions, we have evaluated samples simulated by GENOME to verify that GENOME provides the expected LD patterns and frequency spectra. The program can be used to study the sampling properties of any statistic for a whole genome study. AVAILABILITY: The program and C++ source code are available online at http://www.sph.umich.edu/csg/liang/genome/
Following (19)
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Elliot S Gershon
University of Chicago -
Chunyu Liu
University of Illinois at Chicago -
Stephan F Taylor
University of Michigan -
Margit Burmeister
University of Michigan -
Francis J Mcmahon
National Institutes of Health
