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1.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
2.  The Association of Telomere Length with Colorectal Cancer Differs by the Age of Cancer Onset 
Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length.
In this case–control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls.
Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80–99 percentiles) had a 2–6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1–10 percentiles) had 2–12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner.
Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.
PMCID: PMC3972691  PMID: 24598784
3.  Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke 
Cancer discovery  2011;1(5):420-429.
Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 SNPs in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke Another promising candidate was a SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment, (second hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.
PMCID: PMC3919666  PMID: 22586632
lung cancer; never smokers; inflammation genes; sidestream exposure
4.  Association of GATA4 sequence variation with alcohol dependence 
Addiction biology  2012;10.1111/j.1369-1600.2012.00482.x.
To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis (PCA). Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene-level (p=0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.
PMCID: PMC3504631  PMID: 22862823
GATA4; Alcohol dependence; Genetic association; Gene level test
5.  Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer 
Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk.
We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype.
Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status for these 1,993 CpGs was found to be highly consistent with the results of previously published, independent study that consisted of peripheral blood DNA methylation signatures in 131 pretreatment cases and 274 controls. Implementation of the CIT test revealed 17 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. Of these 13 CpGs, several are associated with immune related genes and genes that have been previously shown to exhibit altered expression in the context of cancer.
These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility.
PMCID: PMC3916313  PMID: 24479488
Integrative genomics; Ovarian cancer; Blood-based DNA methylation
6.  Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states 
Synthetic kappa-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects, and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol dependent subjects and investigated their association with (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations (IDTS); (2), a self-reported history of depression; and, (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II (BDI). In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p=0.00079) and with negative craving (p=0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p=0.024) and alcohol dependence (p=0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol dependent subjects.
PMCID: PMC3901318  PMID: 23101464
OPRK1; PDYN; Alcohol dependence; Craving; Depression
7.  Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer 
Shen, Hui | Fridley, Brooke L. | Song, Honglin | Lawrenson, Kate | Cunningham, Julie M. | Ramus, Susan J. | Cicek, Mine S. | Tyrer, Jonathan | Stram, Douglas | Larson, Melissa C. | Köbel, Martin | Ziogas, Argyrios | Zheng, Wei | Yang, Hannah P. | Wu, Anna H. | Wozniak, Eva L. | Woo, Yin Ling | Winterhoff, Boris | Wik, Elisabeth | Whittemore, Alice S. | Wentzensen, Nicolas | Weber, Rachel Palmieri | Vitonis, Allison F. | Vincent, Daniel | Vierkant, Robert A. | Vergote, Ignace | Van Den Berg, David | Van Altena, Anne M. | Tworoger, Shelley S. | Thompson, Pamela J. | Tessier, Daniel C. | Terry, Kathryn L. | Teo, Soo-Hwang | Templeman, Claire | Stram, Daniel O. | Southey, Melissa C. | Sieh, Weiva | Siddiqui, Nadeem | Shvetsov, Yurii B. | Shu, Xiao-Ou | Shridhar, Viji | Wang-Gohrke, Shan | Severi, Gianluca | Schwaab, Ira | Salvesen, Helga B. | Rzepecka, Iwona K. | Runnebaum, Ingo B. | Rossing, Mary Anne | Rodriguez-Rodriguez, Lorna | Risch, Harvey A. | Renner, Stefan P. | Poole, Elizabeth M. | Pike, Malcolm C. | Phelan, Catherine M. | Pelttari, Liisa M. | Pejovic, Tanja | Paul, James | Orlow, Irene | Omar, Siti Zawiah | Olson, Sara H. | Odunsi, Kunle | Nickels, Stefan | Nevanlinna, Heli | Ness, Roberta B. | Narod, Steven A. | Nakanishi, Toru | Moysich, Kirsten B. | Monteiro, Alvaro N.A. | Moes-Sosnowska, Joanna | Modugno, Francesmary | Menon, Usha | McLaughlin, John R. | McGuire, Valerie | Matsuo, Keitaro | Adenan, Noor Azmi Mat | Massuger, Leon F.A. G. | Lurie, Galina | Lundvall, Lene | Lubiński, Jan | Lissowska, Jolanta | Levine, Douglas A. | Leminen, Arto | Lee, Alice W. | Le, Nhu D. | Lambrechts, Sandrina | Lambrechts, Diether | Kupryjanczyk, Jolanta | Krakstad, Camilla | Konecny, Gottfried E. | Kjaer, Susanne Krüger | Kiemeney, Lambertus A. | Kelemen, Linda E. | Keeney, Gary L. | Karlan, Beth Y. | Karevan, Rod | Kalli, Kimberly R. | Kajiyama, Hiroaki | Ji, Bu-Tian | Jensen, Allan | Jakubowska, Anna | Iversen, Edwin | Hosono, Satoyo | Høgdall, Claus K. | Høgdall, Estrid | Hoatlin, Maureen | Hillemanns, Peter | Heitz, Florian | Hein, Rebecca | Harter, Philipp | Halle, Mari K. | Hall, Per | Gronwald, Jacek | Gore, Martin | Goodman, Marc T. | Giles, Graham G. | Gentry-Maharaj, Aleksandra | Garcia-Closas, Montserrat | Flanagan, James M. | Fasching, Peter A. | Ekici, Arif B. | Edwards, Robert | Eccles, Diana | Easton, Douglas F. | Dürst, Matthias | du Bois, Andreas | Dörk, Thilo | Doherty, Jennifer A. | Despierre, Evelyn | Dansonka-Mieszkowska, Agnieszka | Cybulski, Cezary | Cramer, Daniel W. | Cook, Linda S. | Chen, Xiaoqing | Charbonneau, Bridget | Chang-Claude, Jenny | Campbell, Ian | Butzow, Ralf | Bunker, Clareann H. | Brueggmann, Doerthe | Brown, Robert | Brooks-Wilson, Angela | Brinton, Louise A. | Bogdanova, Natalia | Block, Matthew S. | Benjamin, Elizabeth | Beesley, Jonathan | Beckmann, Matthias W. | Bandera, Elisa V. | Baglietto, Laura | Bacot, François | Armasu, Sebastian M. | Antonenkova, Natalia | Anton-Culver, Hoda | Aben, Katja K. | Liang, Dong | Wu, Xifeng | Lu, Karen | Hildebrandt, Michelle A.T. | Schildkraut, Joellen M. | Sellers, Thomas A. | Huntsman, David | Berchuck, Andrew | Chenevix-Trench, Georgia | Gayther, Simon A. | Pharoah, Paul D.P. | Laird, Peter W. | Goode, Ellen L. | Pearce, Celeste Leigh
Nature communications  2013;4:10.1038/ncomms2629.
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
PMCID: PMC3848248  PMID: 23535649
8.  Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and potentially other non-Hodgkin lymphoma subtypes 
British journal of haematology  2012;159(5):572-576.
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
PMCID: PMC3614403  PMID: 23025533
CLL; NHL; SNPs; BAK1; risk locus
9.  ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium 
Cancer causes & control : CCC  2012;23(11):1805-1810.
Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.
In 8 studies participating in the Ovarian Cancer Association Consortium (OCAC), we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.
Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95% CI: 1.01–1.18; p=0.03). In diplotype analysis, the AO, but not the AA diplotype was associated with increased risk (AO: OR: 1.11; 95% CI: 1.01–1.22; p=0.03; AA: OR: 1.03; 95% CI: 0.87–1.21; p=0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.
Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.
PMCID: PMC3474344  PMID: 22961099
ovarian cancer; ABO blood group; Ovarian Cancer Association Consortium (OCAC); genetic epidemiology
10.  A Two-Stage Evaluation of Genetic Variation in Immune and Inflammation Genes with Risk of Non-Hodgkin Lymphoma Identifies New Susceptibility Locus in 6p21.3 Region 
Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology.
To identify susceptibility immune genes, we conducted a 2-stage analysis of single nucleotide polymorphisms (SNPs) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the Odds Ratios (ORs) and 95% confidence intervals (CI).
In the pooled analysis, only the TAP2 coding SNP rs241447 (MAF=0.26; Thr655Ala) at 6p21.3 (OR=1.34, 95%CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (p=3.1 × 10−5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR=1.82, 95%CI 1.46-2.26; p=6.9 × 10−8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR=1.38, 95% CI 1.08-1.77; p=0.011), but not chronic lymphocytic leukemia (OR=1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors.
Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3.
Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
PMCID: PMC3467356  PMID: 22911334
genetics; non-Hodgkin lymphoma; immune function; single nucleotide polymorphisms
11.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer 
Pharoah, Paul D. P. | Tsai, Ya-Yu | Ramus, Susan J. | Phelan, Catherine M. | Goode, Ellen L. | Lawrenson, Kate | Price, Melissa | Fridley, Brooke L. | Tyrer, Jonathan P. | Shen, Howard | Weber, Rachel | Karevan, Rod | Larson, Melissa C. | Song, Honglin | Tessier, Daniel C. | Bacot, François | Vincent, Daniel | Cunningham, Julie M. | Dennis, Joe | Dicks, Ed | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Armasu, Sebastian M. | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brenton, James D. | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Campbell, Ian | Carney, Michael E | Carvalho, Renato S. | Chang-Claude, Jenny | Chen, Y. Anne | Chen, Zhihua | Chow, Wong-Ho | Cicek, Mine S. | Coetzee, Gerhard | Cook, Linda S. | Cramer, Daniel W. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David | Flanagan, James | Gao, Yu-Tang | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham | Gjyshi, Anxhela | Gore, Martin | Gronwald, Jacek | Guo, Qi | Halle, Mari K | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Estrid | Høgdall, Claus K. | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Kalli, Kimberly R. | Karlan, Beth Y. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Konecny, Gottfried E. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Nathan | Lee, Janet | Leminen, Arto | Lim, Boon Kiong | Lissowska, Jolanta | Lubiński, Jan | Lundvall, Lene | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara | Orlow, Irene | Paul, James | Pejovic, Tanja | Pelttari, Liisa M | Permuth-Wey, Jenny | Pike, Malcolm C | Poole, Elizabeth M | Qu, Xiaotao | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo | Rzepecka, Iwona K | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shen, Hui | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Sieh, Weiva | Southey, Melissa C. | Spellman, Paul | Tajima, Kazuo | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tworoger, Shelley S. | van Altena, Anne M. | Berg, David Van Den | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Goodman, Marc T. | Hall, Per | Easton, Douglas F | Pearce, Celeste L | Berchuck, Andrew | Chenevix-Trench, Georgia | Iversen, Edwin | Monteiro, Alvaro N.A. | Gayther, Simon A. | Schildkraut, Joellen M. | Sellers, Thomas A.
Nature genetics  2013;45(4):362-370e2.
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer.
PMCID: PMC3693183  PMID: 23535730
12.  A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q 
To identify venous thromboembolism (VTE) disease-susceptibility genes.
We performed in silico genome wide association (GWAS) analyses using genotype data imputed to ~2.5 million single nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency-matched on age and sex (n=1459; discovery population). SNPs exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were resequenced.
Seven SNPs exceeded genome-wide significance (P < 5 × 10-8); four on chromosome 1q24.2 (F5 rs6025 [Factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7, and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO resequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3’ UTR that were strongly associated with VTE (P < 10-4) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (α=1 × 10-8; 1% VTE prevalence).
Aside from F5 rs6025, ABO rs8176719 and rs2519093, and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.
PMCID: PMC3419811  PMID: 22672568
venous thromboembolism; deep vein thrombosis; pulmonary embolism; genetics; genome-wide scan; epidemiology
13.  Genomic determinants of motor and cognitive outcomes in Parkinson’s disease 
Parkinsonism & related disorders  2012;18(7):881-886.
Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson’s disease (PD).
To identify common genetic variants associated with motor and cognitive outcomes in PD.
The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn-Yahr Stage ≥4 (motor outcome), and either TICS-M ≤27 or AD-8 ≥2 (cognitive outcomes).
The SNP rs10958605 in the C8orf4 gene had the smallest p-value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42 – 2.31; p = 1.51 × 10−6). The SNP rs6482992 in the CLRN3 gene had the smallest p-value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47–2.79, p = 4.08 × 10−6). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p-values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.
This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.
PMCID: PMC3606821  PMID: 22658654
Genome wide association studies; Parkinson’s disease; outcomes
14.  The genomic landscape of small intestine neuroendocrine tumors 
The Journal of Clinical Investigation  2013;123(6):2502-2508.
Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0–0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.
PMCID: PMC3668835  PMID: 23676460
15.  Common Variants in PARK Loci and Related Genes and Parkinson’s Disease 
Rare mutations in PARK loci genes cause Parkinson’s disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. 1,103 PD cases from the upper Midwest, USA were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species-conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats (VNTRs) in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case-control analyses were performed to study association with PD susceptibility, while cases-only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64 – 0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P-values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility, but show limited association of other PARK loci and related genes with PD.
PMCID: PMC3606822  PMID: 21412835
16.  Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer 
Chronic Obstructive Pulmonary Disease (COPD) is a strong risk factor for lung cancer. Published studies regarding variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive.
We evaluated 470 single nucleotide polymorphisms (SNPs) from 56 genes of these 3 pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established.
Twenty-one SNPs were found to be significantly associated with risk of COPD (P<0.01); gene-based analyses confirmed 2 genes (GCLC and GSS) and identified 3 additional (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; 8 SNPs altered COPD risk with lung cancer 3.1-fold, and 4 SNPs altered the risk without lung cancer 2.3-fold.
Our findings indicate that multiple genetic variations in the 3 selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both.
PMCID: PMC3414259  PMID: 22044695
Chronic Obstructive Pulmonary Disease; Glutathione Metabolism Pathway; DNA Repair Pathway; Inflammatory Response Pathway
17.  Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer 
There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.
Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histological subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.
Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared to women in the lowest (95% CI 1.48-1.84). Analyses by histological subtype yielded risk differences across subtype for endometriosis (phet<0.001), parity (phet<0.01), and tubal ligation (phet=0.041).
The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of each risk factor's effect, which sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histological subtype is warranted.
PMCID: PMC3963289  PMID: 23462924
Gene-environment interactions; ovarian cancer; epidemiology; histological subtype; pooled analysis
18.  Inherited Variants in Regulatory T Cell Genes and Outcome of Ovarian Cancer 
PLoS ONE  2013;8(1):e53903.
Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10−5), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10−4, and rs3753348, p = 9.0×10−4, respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10−4). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10−4) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.
PMCID: PMC3559692  PMID: 23382860
19.  Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria 
Archives of neurology  2011;68(10):1295-1302.
Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.
To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.
An American kindred of Northern European and Cherokee American Indian descent.
Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.
Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.
PMCID: PMC3543870  PMID: 21987543
21.  Evaluating the Influence of Quality Control Decisions and Software Algorithms on SNP Calling for the Affymetrix 6.0 SNP Array Platform 
Human Heredity  2011;71(4):221-233.
Our goal was to evaluate the influence of quality control (QC) decisions using two genotype calling algorithms, CRLMM and Birdseed, designed for the Affymetrix SNP Array 6.0.
Various QC options were tried using the two algorithms and comparisons were made on subject and call rate and on association results using two data sets.
For Birdseed, we recommend using the contrast QC instead of QC call rate for sample QC. For CRLMM, we recommend using the signal-to-noise rate ≥4 for sample QC and a posterior probability of 90% for genotype accuracy. For both algorithms, we recommend calling the genotype separately for each plate, and dropping SNPs with a lower call rate (<95%) before evaluating samples with lower call rates. To investigate whether the genotype calls from the two algorithms impacted the genome-wide association results, we performed association analysis using data from the GENOA cohort; we observed that the number of significant SNPs were similar using either CRLMM or Birdseed.
Using our suggested workflow both algorithms performed similarly; however, fewer samples were removed and CRLMM took half the time to run our 854 study samples (4.2 h) compared to Birdseed (8.4 h).
PMCID: PMC3136375  PMID: 21734406
Genotype call; Birdseed; CRLMM; Quality control decisions; Association
22.  Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy †, ‡ 
Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate SNPs/genes, we performed a genome-wide association study (GWAS) for cisplatin cytotoxicity using lymphoblastoid cell lines (LCLs), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
Experimental Design
GWAS for cisplatin were performed with 283 ethnically diverse LCLs. 168 top SNPs were genotyped in 222 small cell and 961 non-small cell lung cancer (SCLC, NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.
Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the four top SNPs and 8 genes for which expression was correlated with three SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.
This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer.
PMCID: PMC3167019  PMID: 21775533
Lung cancer; cisplatin; pharmacogenomics; lymphoblastoid cell lines; GWAS
23.  Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes 
Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single nucleotide polymorphism (SNP) individually may not be well-suited to detect small effects of multiple SNPs, such as those operating within the same biological pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes.
To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWASes (N cases = 2,813, N deaths = 1,116), with a novel Principal Component – Gamma GSA method. Analysis was completed for all cases and then separately for high grade serous (HGS) histological subtype.
Analysis of the HGS subjects resulted in 43 gene sets with p<0.005 (1.7%); of these, 21 gene sets had p < 0.10 in both GWASes, including intracellular signaling pathway (p = 7.3 × 10−5) and macrolide binding (p = 6.2 ×10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (p=6.3 ×10−4) and macrolide binding (p=1.0×10−3). Of 18 gene sets with p<0.005 (0.7%), eight had p < 0.10 in both GWASes.
This research detected novel gene sets associated with EOC survival.
Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies.
PMCID: PMC3297690  PMID: 22302016
pathway analysis; genetic association; GWAS; SNPs; gynecologic neoplasm
24.  Germline Copy Number Variation and Ovarian Cancer Survival 
Frontiers in Genetics  2012;3:142.
Copy number variants (CNVs) have been implicated in many complex diseases. We examined whether inherited CNVs were associated with overall survival among women with invasive epithelial ovarian cancer. Germline DNA from 1,056 cases (494 deceased, average of 3.7 years follow-up) was interrogated with the Illumina 610 quad genome-wide array containing, after quality control exclusions, 581,903 single nucleotide polymorphisms (SNPs) and 17,917 CNV probes. Comprehensive analysis capitalized upon the strengths of three complementary approaches to CNV classification. First, to identify small CNVs, single markers were evaluated and, where associated with survival, consecutive markers were combined. Two chromosomal regions were associated with survival using this approach (14q31.3 rs2274736 p = 1.59 × 10−6, p = 0.001; 22q13.31 rs2285164 p = 4.01 × 10−5, p = 0.009), but were not significant after multiple testing correction. Second, to identify large CNVs, genome-wide segmentation was conducted to characterize chromosomal gains and losses, and association with survival was evaluated by segment. Four regions were associated with survival (1q21.3 loss p = 0.005, 5p14.1 loss p = 0.004, 9p23 loss p = 0.002, and 15q22.31 gain p = 0.002); however, again, after correcting for multiple testing, no regions were statistically significant, and none were in common with the single marker approach. Finally, to evaluate associations with general amounts of copy number changes across the genome, we estimated CNV burden based on genome-wide numbers of gains and losses; no associations with survival were observed (p > 0.40). Although CNVs that were not well-covered by the Illumina 610 quad array merit investigation, these data suggest no association between inherited CNVs and survival after ovarian cancer.
PMCID: PMC3413872  PMID: 22891074
association testing; copy number variation; genotyping array; ovarian cancer; overall survival
25.  Assessment of hepatocyte growth factor in ovarian cancer mortality 
Invasive ovarian cancer is a significant cause of gynecologic cancer mortality.
We examined whether this mortality was associated with inherited variation in ~170 candidate genes/regions (993 SNPs) in a multi-stage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue micro-arrays (TMAs, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths).
The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR 1.7, 95% CI 1.3–2.2, p=2.0×10−5) and with overall variation in HGF (gene-level test, p=3.7×10−4). Analysis of TCGA data revealed consistent associations (e.g., rs5745709 [r2=0.96 with rs1800793]: TCGA 2.4, 1.4–4.1, p=2.2×10−3; Mayo Clinic+TCGA 1.6, 1.3–1.9, p=7.0×10−5) and suggested genotype correlation with reduced HGF mRNA levels (p=0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET, and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (p=0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (1.0, 0.9–1.1, p=0.87).
We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that genetic variation plays a major role in ovarian cancer mortality; any minor role is not related to genetically-determined expression.
Our study demonstrates the utility of multiple data types and multiple datasets in observational studies.
PMCID: PMC3153603  PMID: 21724856
gynecologic neoplasms; angiogenesis; single nucleotide polymorphism

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