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Search Results: 1 - 10 of 212596 matches for " Susan L Neuhausen "
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Founder populations and their uses for breast cancer genetics
Susan L Neuhausen
Breast Cancer Research , 2000, DOI: 10.1186/bcr36
Abstract: Ethnic differences in the prevalences of many diseases have been observed. For example, sickle-cell anemia in individuals of African descent, Tay-Sachs disease in Ashkenazi Jews [1], and approximately 30 diseases in Finland [2] are more prevalent than in other populations. A likely reason for a preponderance of a disease in a specific population is a founder effect. Founder effects occur when a population is established by a small number of people or when a bottleneck occurs that reduces the population to a small number. When population expansion occurs, the mutation in a founder becomes prevalent in a larger proportion of the population. There may also be a selective advantage to the mutation carrier. By following genetic relationships over many generations, the significance of founder effects can be studied. Diamond and Rotter [3] reviewed studies of the Afrikaner population of South Africa. In 1652, one founding immigrant carried a gene for Huntington's chorea and one brother-sister pair carried a gene for lipoid proteinosis. The result of founder effects is that these diseases are more common in South Africa than in Holland from where the carriers emigrated.Founder populations can be useful in genetic studies, particularly for genetic mapping of complex traits. There is little genetic heterogeneity, so that the majority of individuals with disease will carry the same gene mutation. Linkage disequilibrium between the site of the gene and close markers will exist, so that shared regions of the genome cosegregating with disease can be more readily discerned. As an example, Hirschprung's disease has been described in individuals of many different backgrounds. Using a Mennonite population, in which all affected individuals could be traced to a single common ancestral couple, one of the genes for the disease was localized and subsequently identified [4].Once founder mutations are identified, researchers are able to examine prevalence of mutations in different populati
Human Nail Clippings as a Source of DNA for Genetic Studies  [PDF]
Le Truong, Hannah Lui Park, Seong Sil Chang, Argyrios Ziogas, Susan L. Neuhausen, Sophia S. Wang, Leslie Bernstein, Hoda Anton-Culver
Open Journal of Epidemiology (OJEpi) , 2015, DOI: 10.4236/ojepi.2015.51006
Abstract: Blood samples have traditionally been used as the main source of DNA for genetic analysis. How-ever, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood sam-ples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
RAD51C Germline Mutations in Breast and Ovarian Cancer Cases from High-Risk Families
Jessica Clague,Greg Wilhoite,Aaron Adamson,Adam Bailis,Jeffrey N. Weitzel,Susan L. Neuhausen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025632
Abstract: BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene.
Linkage analysis of HLA and candidate genes for celiac disease in a North American family-based study
Susan L Neuhausen, Michael Feolo, James Farnham, Linda Book, John J Zone
BMC Medical Genetics , 2001, DOI: 10.1186/1471-2350-2-12
Abstract: DNA samples, from members of 62 families with a minimum of two cases of celiac disease, were genotyped at HLA and at 13 candidate gene regions, including CD4, CTLA4, four T-cell receptor regions, and 7 insulin-dependent diabetes regions. Two-point and multipoint heterogeneity LOD (HLOD) scores were examined.The highest two-point and multipoint HLOD scores were obtained in the HLA region, with a two-point HLOD of 3.1 and a multipoint HLOD of 5.0. For the candidate genes, we found no evidence for linkage.Our significant evidence of linkage to HLA replicates the known linkage and association of HLA with CD. In our families, likely candidate genes did not explain the susceptibility to celiac disease.Celiac disease (CD) is a common, familial, autoimmune gastrointestinal disease. It is caused by sensitivity to the dietary protein gluten, which is present in wheat, rye and barley. Symptoms include growth failure, abdominal pain, and diarrhea. Dermatitis herpetiformis is a cutaneous manifestation of CD. Complications of CD include lymphoma, osteoporosis, anemia, and seizures. The prevalence of CD in the US is 1:250 [1] and the ratio of symptomatic to asymptomatic cases is between 1:5 and 1:7 [2]. Before the advent of serological testing for diagnosing CD, it was considered a rare disease in the US.The clinical standard for diagnosis of CD is a small intestinal biopsy showing villus atrophy and resolution of symptoms on a gluten-free diet. However, small intestinal biopsy is expensive, invasive, and often rejected by the US patient population. The serological IgA endomysial antibody (EMA) test is a screening tool that has greatly facilitated evaluation for CD in people with suggestive symptoms and in high-risk populations. IgA EMA testing has proven to be greater than 95% sensitive for adults and children with classic symptomatic CD [3-10] and greater than 98% specific in controls without known clinical disease [11,12]. It is therefore an inexpensive and specific method of s
Detailed comparison of two popular variant calling packages for exome and targeted exon studies
Charles D. Warden,Aaron W. Adamson,Susan L. Neuhausen,Xiwei Wu
PeerJ , 2015, DOI: 10.7717/peerj.600
Abstract: The Genome Analysis Toolkit (GATK) is commonly used for variant calling of single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compare (1) the effects of different pre-processing steps prior to variant calling with both GATK and VarScan, (2) VarScan variants called with increasingly conservative parameters, and (3) filtered and unfiltered GATK variant calls (for both the UnifiedGenotyper and the HaplotypeCaller). Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets), each with approximately a dozen subjects. In most cases, pre-processing steps (e.g., indel realignment and quality score base recalibration using GATK) had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. Based upon concordance statistics presented in this study, we recommend GATK users focus on “high-quality” GATK variants by filtering out variants flagged as low-quality. We also found that running VarScan with a conservative set of parameters (referred to as “VarScan-Cons”) resulted in a reproducible list of variants, with high concordance (>97%) to high-quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84–88% of the high-quality GATK SNPs in the exome datasets. This study also provides limited evidence that VarScan-Cons has a decreased false positive rate among novel variants (relative to high-quality GATK SNPs) and that the GATK HaplotypeCaller has an increased false positive rate for indels (relative to VarScan-Cons and high-quality GATK UnifiedGenotyper indels). More broadly, we believe the metrics used for comparison in this study can be useful in assessing the quality of variant calls in the context of a specific experimental design. As an example, a limited number of variant calling comparisons are also performed on two additional variant callers.
Detailed comparison of two popular variant calling packages for exome and targeted exon studies
Charles D Warden,Aaron W Adamson,Susan L Neuhausen,Xiwei Wu
PeerJ , 2015, DOI: 10.7287/peerj.preprints.403v3
Abstract: The Genome Analysis Toolkit (GATK) is commonly used for variant calling of single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compared four lists of variants called by GATK (using the UnifiedGenotyper and the HaplotypeCaller algorithms, with and without filtering low quality variants) and three lists of variants called using VarScan (with varying sets of parameters). Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets), each with approximately a dozen subjects. We found that running VarScan with a conservative set of parameters (referred to as “VarScan-Cons”) resulted in a high quality gene list, with high concordance (>97%) when compared to high quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84-88% of the high-quality GATK SNPs in the exome datasets. We also assessed the impact of pre-processing (e.g., indel realignment and quality score base recalibration using GATK). In most cases, these pre-processing steps had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. More broadly, we believe the metrics used for comparison in this study can be useful in assessing the quality of variant calls in the context of a specific experimental design. As an example, a limited number of variant calling comparisons are also performed on two additional variant callers.
Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Independent Susceptibility Loci
Richard Ahn, Yuan Chun Ding, Joseph Murray, Alessio Fasano, Peter H. R. Green, Susan L. Neuhausen, Chad Garner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036926
Abstract: Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region.
Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus
Chad Garner, Richard Ahn, Yuan Chun Ding, Linda Steele, Samantha Stoven, Peter H. Green, Alessio Fasano, Joseph A. Murray, Susan L. Neuhausen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101428
Abstract: We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value <1.0×10?7), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0×10?7 < p-value < 1.0×10?6). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations.
The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort
Eunjung Lee, Fredrick Schumacher, Juan Pablo Lewinger, Susan L Neuhausen, Hoda Anton-Culver, Pamela L Horn-Ross, Katherine D Henderson, Argyrios Ziogas, David Van Den Berg, Leslie Bernstein, Giske Ursin
Breast Cancer Research , 2011, DOI: 10.1186/bcr2859
Abstract: We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT = 0.002; overall PACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT.Reproductive and hormonal factors, including age at menarche, parity, number of full-term pregnancies, age at first full-term pregnancy, breastfeeding, age at menopause, body mass index (BMI), and physical activity, are associated with breast cancer risk [1,2]. Consistent with these observations, breast cancer risk is higher among women with higher circulating levels of endogenous estrogen [3-5] and among women using combine
Recent breast cancer incidence trends according to hormone therapy use: the California Teachers Study cohort
Sarah F Marshall, Christina A Clarke, Dennis Deapen, Katherine Henderson, Joan Largent, Susan L Neuhausen, Peggy Reynolds, Giske Ursin, Pamela L Horn-Ross, Daniel O Stram, Claire Templeman, Leslie Bernstein
Breast Cancer Research , 2010, DOI: 10.1186/bcr2467
Abstract: We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry.During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 2006, incidence had declined 30.6% by 2003 to 2005 (P = 0.001); whereas incidence did not change significantly for those who never took HT (P = 0.33).Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use.Several reports document recent declines in the incidence of invasive breast cancer in the US [1-7] and throughout developed countries [8-13]. The reasons for and timing of these declines is controversial. Most researchers have suggested that the sharp decline observed in 2002 followed widespread reductions in prescribing [14] and use of menopausal
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