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1.  Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort 
PLoS Genetics  2015;11(1):e1004930.
An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that—by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers—we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men’s Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10−12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin’s lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).
Author Summary
An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into existing well-phenotyped cohorts with genome-wide data by using large sequenced reference panels; however, the efficacy of this approach remains controversial. A recent study suggested that it is not possible to impute the rare HOXB13 G84E variant using neighboring SNP markers. We show that by using an enriched reference sequenced sample of 22 mutation carriers, we were able to impute this mutation into a large cohort of 83,285 non-Hispanic White individuals from the Kaiser Permanente Research Program on Genes, Environment, and Health Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The imputation was confirmed via a novel classification and regression tree method, and then empirically validated by direct mutation genotyping of a subset of 1,673 of these individuals in addition to 1,789 other men from Kaiser. Using the same GERA cohort, we then confirmed that the G84E mutation is associated with increased risk of prostate cancer, and estimated the age-specific risk for carriers of the mutation. Finally, we obtained evidence that the mutation is associated with additional types of cancer in the GERA cohort.
PMCID: PMC4309593  PMID: 25629170
2.  Polymorphisms of an Innate Immune Gene, Toll-Like Receptor 4, and Aggressive Prostate Cancer Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(10):e110569.
Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.
We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.
Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.
TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
PMCID: PMC4215920  PMID: 25360682
3.  A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia 
Pediatrics  2013;132(2):290-297.
Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.
The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 250–296/7 weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks’ postmenstrual age. At 36 weeks’ postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.
Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10−8) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.
We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.
PMCID: PMC3727675  PMID: 23897914
genome-wide association study (GWAS); chronic lung disease; genetic predisposition to disease; premature; very low birth weight infant
4.  Hypospadias and genes related to genital tubercle and early urethral development 
The Journal of urology  2013;190(5):1884-1892.
We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans.
Materials and Methods
We examined 293 relatively common tagSNPs in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2, and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population-based non-malformed male controls born in California from 1990-2003.
There were 28 SNPs for which any of the comparisons (i.e., overall or for a specific severity) had a p-value <0.01. The homozygous variant genotypes for four SNPs in BMP7 were associated with at least 2-fold increased risk of hypospadias, regardless of severity. Five SNPs for FGF10 were associated with 3- to 4-fold increased risks, regardless of severity; for four of them, results were restricted to whites. For GLI1, GLI2 and GLI3, there were 12 associated SNPs but results were inconsistent by severity and race-ethnicity. For SHH, one SNP was associated with 2.4-fold increased risk of moderate hypospadias. For WT1, six SNPs were associated with approximately 2-fold increased risks, primarily for severe hypospadias.
This study provides evidence that SNPs in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.
PMCID: PMC4103581  PMID: 23727413
hypospadias; genes; genital tubercle
5.  Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia 
Journal of human genetics  2013;58(6):353-361.
Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a 2-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox proportional hazards model. 154 genetically European patients were used for the primary analysis. An intronic SNP in ABCC3 (rs4148405) was associated with a significantly shorter DFS (HR=3.2, p=5.6 x 10(-6)) in our primary cohort. In addition a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, p=0.001 for 154 European ancestry; HR=1.7, p=0.028 for 125 non-European patients). Thus for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.
PMCID: PMC4068832  PMID: 23677058
6.  Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls 
Human genetics  2013;132(5):579-589.
Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
PMCID: PMC3628758  PMID: 23370545
7.  Genome-Wide Association Studies and Beyond 
Genome-wide association studies (GWAS) provide an important avenue for undertaking an agnostic evaluation of the association between common genetic variants and risk of disease. Recent advances in our understanding of human genetic variation and the technology to measure such variation have made GWAS feasible. Over the past few years a multitude of GWAS have identified and replicated many associated variants. These findings are enriching our knowledge about the genetic basis of disease and leading some to advocate using GWA study results for genetic testing. For many of the GWA study results, however, the underlying mechanisms remain unclear and the findings explain only a limited amount of heritability. These issues may be clarified by more detailed investigations, including analyses of less common variants, sequence-level data, and environmental exposures. Such studies should help clarify the potential value of genetic testing to the public’s health.
PMCID: PMC3997166  PMID: 20235850
copy number; linkage disequilibrium; population stratification; single nucleotide polymorphism; whole genome
8.  Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population 
The Journal of urology  2012;189(1):305-311.
A recent genome-wide association study reported the novel finding that variants in diacylglycerol kinase kappa (DGKK) were associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially-ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.
We examined the association of 27 DGKK SNPs with hypospadias, relative to population-based non-malformed controls born in selected California counties from 1990-2003. Analyses included a maximum of 928 controls and 665 cases (91 mild, 336 moderate, 221 severe, 17 undetermined). Results for mild and moderate cases were similar so they were grouped together.
For mild and moderate cases, odds ratios (OR) for 15 of the 27 SNPs had p-values <0.05; two were <1, and the others ranged from 1.3 to 1.8. Among severe cases, ORs tended to be closer to one and none of the p-values were <0.05. Due to high LD across the SNPs, haplotype analyses were conducted, and two blocks were generated. These analyses identified a set of eight variants that was associated with a three- to four- fold increased risk, relative to the most common haplotype, regardless of severity of the phenotype (the OR was 4.1, p<10-4 for mild to moderate cases and 3.3, p=0.001 for severe cases).
This study confirms that DGKK variants are associated with hypospadias. Further studies are needed to enable a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.
PMCID: PMC3973486  PMID: 23177175
9.  HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease 
Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans.
We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N=2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans.
In our studies the mutation was found exclusively among men with prostate cancer (carrier frequency=1.48%) or unaffected brothers of cases carrying the mutation (frequency=0.34%), and carrying the mutation gave an odds ratio for disease=4.79 (P=0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P=3.5×10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P<1×10−5.
The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
PMCID: PMC3617049  PMID: 23396964
Familial Cancer; Genetic Association; Homeobox; Functional Mutation; Prostate Cancer
10.  The Future of Clinical Trials: A panel discussion 
Statistics in medicine  2012;31(25):10.1002/sim.5484.
A panel discussion on the future of clinical trials addressed several issues raised in the course of the first day of the Workshop. The chair posed questions in six areas which the panel and audience addressed. This paper summarizes the panel discussion.
PMCID: PMC3864589  PMID: 22806631
11.  Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data 
PLoS ONE  2013;8(12):e81503.
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
PMCID: PMC3861317  PMID: 24349080
12.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
PMCID: PMC3694490  PMID: 23583978
13.  A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101 
Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity.
Experimental Design
A prospective pharmacogenetic analysis of primary breast cancer patients randomized to the paclitaxel arm of CALGB 40101 was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was performed and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.
A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort (rs10771973; HR, 1.57; 95% CI, 1.30–1.91; P = 2.6 × 10−6) and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10−3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.
A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.
PMCID: PMC3445665  PMID: 22843789
paclitaxel; peripheral neuropathy; breast cancer; pharmacogenetics; genome-wide association study
14.  Rare Genetic Variants and Treatment Response: Sample Size and Analysis Issues 
Statistics in medicine  2012;31(25):3041-3050.
Incorporating information about common genetic variants may help improve the design and analysis of clinical trials. For example, if genes impact response to treatment, one can pre-genotype potential participants to screen out genetically determined non-responders and substantially reduce the sample size and duration of a trial. Genetic associations with response to treatment are generally much larger than those observed for development of common diseases, as highlighted here by findings from genome-wide association studies. With the development and decreasing cost of next generation sequencing, more extensive genetic information—including rare variants—is becoming available on individuals treated with drugs and other therapies. We can use this information to evaluate whether rare variants impact treatment response. The sparseness of rare variants, however, raises issues of how the resulting data should be best analyzed. As shown here, simply evaluating the association between each rare variant and treatment response one-at-a-time will require enormous sample sizes. Combining the rare variants together can substantially reduce the required sample sizes, but require a number of assumptions about the similarity among the rare variants’ effects on treatment response. We have developed an empirical approach for aggregating and analyzing rare variants that limit such assumptions and work well under a range of scenarios. Such analyses provide a valuable opportunity to more fully decipher the genomic basis of response to treatment.
PMCID: PMC3766744  PMID: 22736504
aggregation; clinical trials; GWAS; pharmacogenomics; rare variants; treatment response
15.  Non-Steroidal Anti-Inflammatory Drugs, Variation in Inflammatory Genes, and Aggressive Prostate Cancer 
Pharmaceuticals (Basel, Switzerland)  2010;3(10):3127-3142.
Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use and the risk of aggressive prostate cancer is modulated by variants in several inflammatory genes. We found that NSAIDs may have differential effects on prostate cancer development, depending on one’s genetic makeup. Further study of these inflammatory pathways may clarify the mechanisms through which NSAIDs impact prostate cancer risk.
PMCID: PMC3766748  PMID: 24023525
prostatic neoplasms; non-steroidal anti-inflammatory agents; aspirin; genetic variation; single nucleotide polymorphism
16.  Segmentation and Estimation for SNP Microarrays: a Bayesian Multiple Change Point Approach 
Biometrics  2010;66(3):675-683.
High-density SNP microarrays provide a useful tool for the detection of copy number variants (CNVs). The analysis of such large amounts of data is complicated, especially with regard to determining where copy numbers change and their corresponding values. In this paper, we propose a Bayesian multiple change point model (BMCP) for segmentation and estimation of SNP microarray data. Segmentation concerns separating a chromosome into regions of equal copy number differences between the sample of interest and some reference, and involves the detection of locations of copy number difference changes. Estimation concerns determining true copy number for each segment. Our approach not only gives posterior estimates for the parameters of interest, namely locations for copy number difference changes and true copy number estimates, but also useful confidence measures. In addition, our algorithm can segment multiple samples simultaneously, and infer both common and rare CNVs across individuals. Finally, for studies of CNVs in tumors, we incorporate an adjustment factor for signal attenuation due to tumor heterogeneity or normal contamination that can improve copy number estimates.
PMCID: PMC3766751  PMID: 19764955
Bayesian multiple change points; copy number variant; estimation; segmentation; signal attenuation; SNP microarrays
17.  Evaluation of Polymorphisms in EWSR1 and Risk of Ewing Sarcoma: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;59(1):52-56.
Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology.
Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests.
One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79 – 21.7; p = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%.
Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be a Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.
PMCID: PMC3204324  PMID: 21793187
Ewing sarcoma; EWSR1; single nucleotide polymorphism; genetic epidemiology
18.  Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent 
Prostate Cancer  2013;2013:560857.
Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.
PMCID: PMC3583061  PMID: 23476788
19.  Next Generation Analytic Tools for Large Scale Genetic Epidemiology Studies of Complex Diseases 
Genetic epidemiology  2011;36(1):22-35.
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.
PMCID: PMC3368075  PMID: 22147673
gene-gene interactions; gene-environment interactions; rare variants; next generation sequencing; complex phenotypes; simulations; computational resources
20.  Copy Number Alterations in Prostate Tumors and Disease Aggressiveness 
Genes, chromosomes & cancer  2011;51(1):66-76.
Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome-wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M SNP array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy-neutral) and 6q (copy-loss). Combined loss and copy-neutral events were associated with increasing disease grade (p=0.03), stage (p=0.01), and diagnostic PSA (p=0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The ‘regulation of apoptosis’ pathway was associated with stage of disease (p=0.004), while the ‘reproductive cellular process’ pathway was associated with diagnostic PSA (p=0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (p=0.007). These findings confirm known regions of CNAs in prostate cancer, and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help clarify the genetic basis of prostate cancer aggressiveness.
PMCID: PMC3209417  PMID: 21965145
21.  Association of the Innate Immunity and Inflammation Pathway with Advanced Prostate Cancer Risk 
PLoS ONE  2012;7(12):e51680.
Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.
PMCID: PMC3522730  PMID: 23272139
22.  The Covariate's Dilemma 
PLoS Genetics  2012;8(11):e1003096.
PMCID: PMC3497901  PMID: 23162385
23.  Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African Americans 
Genes and Immunity  2011;13(3):258-267.
Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter-region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation, and lower levels of inflammation-associated viral replication in HIV-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) (r= −0.38, p=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r= −0.41, p=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r= −0.36, p=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 (sCD14) levels during highly active antiretroviral therapy (HAART) (r= 0.38, p=0.007) as well as higher mean viral load off-therapy (r= 0.24, p=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.
PMCID: PMC3330188  PMID: 22048453
Heme oxygenase-1; microsatellite; polymorphism; HIV; soluble CD14; monocytes
24.  Impact of consumption of vegetable, fruit, grain, and high glycemic index foods on aggressive prostate cancer risk 
Nutrition and cancer  2011;63(6):860-872.
Prostate cancer is a common but complex disease, and distinguishing modifiable risk factors such as diet for more aggressive disease is extremely important. Previous work has detected intriguing associations between vegetable, fruit, and grains and more aggressive prostate cancer, although these remain somewhat unclear. Here we further investigate such potential relationships with a case-control study of 982 men (470 more aggressive prostate cancer cases and 512 control subjects). Comparing the highest to lowest quartiles of intake, we found that increasing intakes of leafy vegetables were inversely associated with risk of aggressive prostate cancer (adjusted odds ratio (OR) =0.66, 95% CI: 0.46, 0.96, P-trend=0.02), as was higher consumption of high carotenoid vegetables (OR=0.71, 95% CI: 0.48, 1.04; P-trend=0.04). Conversely, increased consumption of high glycemic index foods were positively associated with risk of aggressive disease (OR=1.64, 95% CI: 1.05, 2.57; P-trend=0.02). These results were driven by a number of specific foods within the food groups. Our findings support the hypothesis that diets high in vegetables and low in high glycemic index foods decrease risk of aggressive prostate cancer.
PMCID: PMC3209415  PMID: 21774611
Diet; aggressive prostate cancer
25.  Polygenic Modeling of Genome-Wide Association Studies: An Application to Prostate and Breast Cancer 
Genome-wide association studies (GWAS) have successfully detected and replicated associations with numerous diseases, including cancers of the prostate and breast. These findings are helping clarify the genomic basis of such diseases, but appear to explain little of disease heritability. This limitation might reflect the focus of conventional GWAS on a small set of the most statistically significant associations with disease. More information might be obtained by analyzing GWAS using a polygenic model, which allows for the possibility that thousands of genetic variants could impact disease. Furthermore, there may exist common polygenic effects between potentially related phenotypes (e.g., prostate and breast cancer). Here we present and apply a polygenic model to GWAS of prostate and breast cancer. Our results indicate that the polygenic model can explain an increasing—albeit low—amount of heritability for both of these cancers, even when excluding the most statistically significant associations. In addition, nonaggressive prostate cancer and breast cancer appear to share a common polygenic model, potentially reflecting a similar underlying biology. This supports the further development and application of polygenic models to genomic data.
PMCID: PMC3125548  PMID: 21348634

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