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1.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russell, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojensen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(20):4239.
PMCID: PMC3871151
2.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs
3.  A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication 
Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
PMCID: PMC3781176  PMID: 23423446
Postmenopausal breast cancer risk; Menopausal hormone therapy; Polymorphisms; Gene-environment interaction; Genome-wide association study; Case-only study
4.  Joint Effects of Colorectal Cancer Susceptibility Loci, Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer 
PLoS ONE  2014;9(3):e92212.
Genome wide association studies (GWAS) have identified several SNPs associated with colorectal cancer (CRC) susceptibility. Vitamin D is also inversely associated with CRC risk.
We examined main and joint effects of previously GWAS identified genetic markers of CRC and plasma 25-hydroxyvitamin D (25(OH)D) on CRC risk in three prospective cohorts: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Physicians' Health Study (PHS). We included 1895 CRC cases and 2806 controls with genomic DNA. We calculated odds ratios and 95% confidence intervals for CRC associated with additive genetic risk scores (GRSs) comprised of all CRC SNPs and subsets of these SNPs based on proximity to regions of increased vitamin D receptor binding to vitamin D response elements (VDREs), based on published ChiP-seq data. Among a subset of subjects with additional prediagnostic 25(OH)D we tested multiplicative interactions between plasma 25(OH)D and GRS's. We used fixed effects models to meta-analyze the three cohorts.
The per allele multivariate OR was 1.12 (95% CI, 1.06–1.19) for GRS-proximalVDRE; and 1.10 (95% CI, 1.06–1.14) for GRS-nonproxVDRE. The lowest quartile of plasma 25(OH)D compared with the highest, had a multivariate OR of 0.63 (95% CI, 0.48–0.82) for CRC. We did not observe any significant interactions between any GRSs and plasma 25(OH)D.
We did not observe evidence for the modification of genetic susceptibility for CRC according to vitamin D status, or evidence that the effect of common CRC risk alleles differed according to their proximity to putative VDR binding sites.
PMCID: PMC3966783  PMID: 24670869
5.  Glatiramer acetate does not protect from acute ischemic stroke in mice 
The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis.
We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1.
Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia.
PMCID: PMC3943273  PMID: 24576335
Glatiramer acetate; Stroke; Inflammation; Neurodegeneration
6.  Oligodendroglial p130Cas Is a Target of Fyn Kinase Involved in Process Formation, Cell Migration and Survival 
PLoS ONE  2014;9(2):e89423.
Oligodendrocytes are the myelinating glial cells of the central nervous system. In the course of brain development, oligodendrocyte precursor cells migrate, scan the environment and differentiate into mature oligodendrocytes with multiple cellular processes which recognize and ensheath neuronal axons. During differentiation, oligodendrocytes undergo dramatic morphological changes requiring cytoskeletal rearrangements which need to be tightly regulated. The non-receptor tyrosine kinase Fyn plays a central role in oligodendrocyte differentiation and myelination. In order to improve our understanding of the role of oligodendroglial Fyn kinase, we have identified Fyn targets in these cells. Purification and mass-spectrometric analysis of tyrosine-phosphorylated proteins in response to overexpressed active Fyn in the oligodendrocyte precursor cell line Oli-neu, yielded the adaptor molecule p130Cas. We analyzed the function of this Fyn target in oligodendroglial cells and observed that reduction of p130Cas levels by siRNA affects process outgrowth, the thickness of cellular processes and migration behavior of Oli-neu cells. Furthermore, long term p130Cas reduction results in decreased cell numbers as a result of increased apoptosis in cultured primary oligodendrocytes. Our data contribute to understanding the molecular events taking place during oligodendrocyte migration and morphological differentiation and have implications for myelin formation.
PMCID: PMC3931761  PMID: 24586768
7.  Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer 
PLoS Genetics  2014;10(2):e1004129.
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Author Summary
Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases.
PMCID: PMC3923678  PMID: 24550738
8.  A Genome-Wide “Pleiotropy Scan” Does Not Identify New Susceptibility Loci for Estrogen Receptor Negative Breast Cancer 
PLoS ONE  2014;9(2):e85955.
Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”.
PMCID: PMC3921107  PMID: 24523857
9.  Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma 
Nature genetics  2013;45(7):799-803.
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
PMCID: PMC3910497  PMID: 23727862
10.  A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts 
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
PMCID: PMC3545904  PMID: 23243202
11.  Exploring the genetic architecture of circulating 25-hydroxyvitamin D 
Genetic epidemiology  2012;37(1):92-98.
The primary circulating form of vitamin D is 25-hydroxy-vitamin D (25(OH)D), a modifiable trait linked with a growing number of chronic diseases. In addition to environmental determinants of 25(OH)D, including dietary sources and skin ultraviolet B (UVB) exposure, twin and family-based studies suggest that genetics contribute substantially to vitamin D variability with heritability estimates ranging from 43% to 80%. Genome-wide association studies (GWAS) have identified SNPs located in four gene regions associated with 25(OH)D. These SNPs collectively explain only a fraction of the heritability in 25(OH)D estimated by twin and family based studies. Using 25(OH)D concentrations and GWAS data on 5,575 subjects drawn from 5 cohorts, we hypothesized that genome-wide data, in the form of (1) a polygenic score comprised of hundreds or thousands of SNPs that do not individually reach GWAS significance, or (2) a linear-mixed-model for genome-wide complex trait analysis, would explain variance in measured circulating 25(OH)D beyond that explained by known genome-wide significant 25(OH)D associated SNPs. GWAS identified SNPs explained 5.2% of the variation in circulating 25(OH)D in these samples and there was little evidence additional markers significantly improved predictive ability. On average a polygenic score comprised of GWAS identified SNPs explained a larger proportion of variation in circulating 25(OH)D than scores comprised of thousands of SNPs which were on average, non-significant. Employing a linear-mixed-model for genome-wide complex trait analysis explained little additional variability (range 0-22%). The absence of a significant polygenic effect in this relatively large sample suggests an oligogenetic architecture for 25(OH)D.
PMCID: PMC3524394  PMID: 23135809
vitamin D; heritability; genome wide association; polygenic score
12.  Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium 
Cancer causes & control : CCC  2012;24(1):13-25.
Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).
The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case–control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.
Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2–8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).
These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
PMCID: PMC3529822  PMID: 23112111
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
13.  Common genetic variation of the calcium sensing receptor and lethal prostate cancer risk 
Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether 1) common genetic variation in CaSR was associated with PCa risk and 2) these associations varied by calcium intake or plasma 25-hydroxyvitamin D (25(OH)D) levels.
We included 1193 PCa cases and 1244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR SNPs to capture common variation. The main outcome was risk of lethal PCa (n=113); secondary outcomes were overall (n=1193) and high-grade PCa (n=225). We used the kernel machine approach to conduct a gene-level multi-marker analysis and unconditional logistic regression to compute per-allele odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs.
The joint association of SNPs in CaSR was significant for lethal PCa (p=0.04); this association was stronger in those with low 25(OH)D (p=0.009). No individual SNPs were associated after considering multiple testing; 3 SNPs were nominally associated (p<0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89)): rs13083990; and 1.55(1.09-2.20): rs2270916. The 3 non-synonymous SNPs (rs1801725, rs1042636, rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D (OR(95%CI): 0.54(0.31-0.95)). There were no significant associations with overall or high-grade PCa.
Our findings indicate that CaSR may be involved in PCa progression.
Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.
PMCID: PMC3538912  PMID: 23125333
molecular and genetic epidemiology; prostate cancer; vitamin D, calcium; CaSR
14.  Prospective study of effect modification by Toll-Like Receptor 4 variation on the association between Trichomonas vaginalis serostatus and prostate cancer 
Cancer causes & control : CCC  2012;24(1):175-180.
In previous studies, we observed a positive association between Trichomonas vaginalis serostatus and risk of prostate cancer, particularly aggressive cancer, which we hypothesized might be due to T. vaginalis-mediated intraprostatic inflammation and cell damage. To explore this hypothesis further, we investigated effect modification by Toll-like receptor 4 (TLR4) variation on this association. We hypothesized that TLR4 variation might serve a marker of the anti-trichomonad immune response because T. vaginalis has been shown to elicit inflammation through this receptor.
We previously genotyped the non-synonymous TLR4 single nucleotide polymorphism (SNP), rs4986790, and determined T. vaginalis serostatus for 690 incident prostate cancer cases and 692 controls in a nested case-control study within the Health Professionals Follow-up Study.
A non-significant suggestion of effect modification was observed by rs4986790 carrier status on the association between T. vaginalis serostatus and prostate cancer risk (p-interaction=0.07). While no association was observed among men homozygous wildtype for this SNP (odds ratio (OR)=1.23, 95% confidence interval (CI): 0.86–1.77), a positive association was observed among variant carriers (OR=4.16, 95% CI: 1.32–13.1).
Although not statistically significant, TLR4 variation appeared to influence the association between T. vaginalis serostatus and prostate cancer risk consistent with the hypothesis that inflammation plays a role in this association. Larger studies will be necessary to explore this possible effect modification further.
PMCID: PMC3549464  PMID: 23179660
Toll-like receptor 4; T. vaginalis; prostate cancer; SNP; aspirin
15.  Genome-Wide Association Study of Survival in Patients with Pancreatic Adenocarcinoma 
Gut  2012;63(1):10.1136/gutjnl-2012-303477.
Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.
We analyzed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1,005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (P≤10−5) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).
In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21, and 1p36.13, tagged by rs12362504 (P=1.63×10−7), rs981621 (P=1.65×10−7), and rs16861827 (P=3.75×10−7), respectively. One-hundred thirty-one SNPs with P ≤ 10−5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; P=1.72×10−7) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The hazard ratio (95% CI) for death was 0.74 (0.66–0.84) in PanScan I, 0.79 (0.65–0.97) in ChinaPC, and 0.76 (0.68–0.84) in the joint analysis.
Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.
PMCID: PMC3816124  PMID: 23180869
Pancreatic cancer; GWAS; single nucleotide polymorphism; SET binding factor 2
17.  Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2012;176(12):1121-1129.
Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases.
PMCID: PMC3571230  PMID: 23193118
carcinoma; diabetes mellitus, type 2; genetic predisposition to disease; genetics; genome-wide association study; humans; polymorphism, single nucleotide; prostatic neoplasms
Rotating night shift work is associated with increased risk of breast cancer, likely via circadian disruption. We hypothesized that circadian pathway genes influence breast cancer risk, particularly in rotating night shift workers. We selected 178 common variants across 15 genes pertinent to the circadian system. Using a mixed candidate- and tag-single nucleotide polymorphism approach, we tested for associations between these variants and breast cancer risk in 1,825 women within the Nurses’ Health Study II cohort and investigated potential interactions between genotype and rotating shift-work in a subset of 1,318 women. Multiple-testing-adjusted p-values were obtained by permutation (n=10,000). None of the selected variants was significantly associated with breast cancer risk. However, when accounting for potential effect modification, rs23051560 (Ala394Thr) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2) was most strongly associated with breast cancer risk (nominal test for interaction p-value=0.0005; 10,000-permutation-based main-effects p-value among women with <24 months of shift-work=0.003). The observed multiplicative association with breast cancer risk per minor allele (A) was 0.65 (95%CI=0.51–0.82) among women with <24 months of shift-work, and 1.19 (95%CI=0.93–1.54) with ≥24 months of shift-work. Women homozygous for the minor allele (AA) with ≥24 months of shift-work had a 2.83-times higher breast cancer risk compared to homozygous AA women with <24 months of shift-work (95%CI=1.47–5.56).
In smmary, common variation in circadian genes plays at most a small role in breast cancer risk among women of European ancestry. The impact of NPAS2 Ala394Thr in the presence of rotating shift-work requires further investigation.
PMCID: PMC3408553  PMID: 22473669
circadian genes; breast cancer; rotating shift work; night work
19.  Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array 
Eeles, Rosalind A | Olama, Ali Amin Al | Benlloch, Sara | Saunders, Edward J | Leongamornlert, Daniel A | Tymrakiewicz, Malgorzata | Ghoussaini, Maya | Luccarini, Craig | Dennis, Joe | Jugurnauth-Little, Sarah | Dadaev, Tokhir | Neal, David E | Hamdy, Freddie C | Donovan, Jenny L | Muir, Ken | Giles, Graham G | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J | Gapstur, Susan | Chanock, Stephen J | Berndt, Sonja I | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J | Travis, Ruth | Campa, Daniele | Ingles, Sue A | John, Esther M | Hayes, Richard B | Pharoah, Paul DP | Pashayan, Nora | Khaw, Kay-Tee | Stanford, Janet | Ostrander, Elaine A | Signorello, Lisa B | Thibodeau, Stephen N | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright,  | Brenner, Hermann | Park, Jong Y | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda B | Clements, Judith A | Teixeira, Manuel R | Dicks, Ed | Lee, Andrew | Dunning, Alison | Baynes, Caroline | Conroy, Don | Maranian, Melanie J | Ahmed, Shahana | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A | Sawyer, Emma J | Morgan, Angela | Dearnaley, David P | Horwich, Alan | Huddart, Robert A | Khoo, Vincent S | Parker, Christopher C | Van As, Nicholas J | Woodhouse, J | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin | Lophatananon, Artitaya | Cox, Angela | Southey, Melissa | Hopper, John L | English, Dallas R | Aly, Markus | Adolfsson, Jan | Xu, Jiangfeng | Zheng, Siqun | Yeager, Meredith | Kaaks, Rudolf | Diver, W Ryan | Gaudet, Mia M | Stern, Mariana | Corral, Roman | Joshi, Amit D | Shahabi, Ahva | Wahlfors, Tiina | Tammela, Teuvo J | Auvinen, Anssi | Virtamo, Jarmo | Klarskov, Peter | Nordestgaard, Børge G | Røder, Andreas | Nielsen, Sune F | Bojesen, Stig E | Siddiq, Afshan | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika | Karyadi, Danielle | Blot, William J | Zheng, Wei | Cai, Qiuyin | McDonnell, Shannon K | Rinckleb, Antje | Drake, Bettina | Colditz, Graham | Wokolorczyk, Dominika | Stephenson, Robert A | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Sellers, Thomas A | Lin, Hui-Yi | Slavov, Chavdar | Mitev, Vanio | Lose, Felicity | Srinivasan, Srilakshmi | Maia, Sofia | Paulo, Paula | Lange, Ethan | Cooney, Kathleen A | Antoniou, Antonis | Vincent, Daniel | Bacot, François | Tessier,  | Kote-Jarai, Zsofia | Easton, Douglas F
Nature genetics  2013;45(4):10.1038/ng.2560.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
PMCID: PMC3832790  PMID: 23535732
20.  Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U.S. Men and Women of European Ancestry 
Annals of internal medicine  2009;150(8):541-550.
Genome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk.
To examine the joint effects of several type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts.
Nested case–control study.
United States.
2809 patients with type 2 diabetes and 3501 healthy control participants of European ancestry from the Health Professionals Follow-up Study and Nurses’ Health Study.
A genetic risk score (GRS) was calculated on the basis of 10 polymorphisms in 9 loci.
After adjustment for age and body mass index (BMI), the odds ratio for type 2 diabetes with each point of GRS, corresponding to 1 risk allele, was 1.19 (95% CI, 1.14 to 1.24) and 1.16 (CI, 1.12 to 1.20) for men and women, respectively. Persons with a BMI of 30 kg/m2 or greater and a GRS in the highest quintile had an odds ratio of 14.06 (CI, 8.90 to 22.18) compared with persons with a BMI less than 25 kg/m2 and a GRS in the lowest quintile after adjustment for age and sex. Persons with a positive family history of diabetes and a GRS in the highest quintile had an odds ratio of 9.20 (CI, 5.50 to 15.40) compared with persons without a family history of diabetes and with a GRS in the lowest quintile. The addition of the GRS to a model of conventional risk factors improved discrimination by 1% (P < 0.001).
The study focused only on persons of European ancestry; whether GRS is associated with type 2 diabetes in other ethnic groups remains unknown.
Although its discriminatory value is currently limited, a GRS that combines information from multiple genetic variants might be useful for identifying subgroups with a particularly high risk for type 2 diabetes.
PMCID: PMC3825275  PMID: 19380854
21.  Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status 
Journal of medical genetics  2012;49(9):601-608.
There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumors with different hormone receptor status.
Material and Methods
Within the Breast and Prostate Cancer Cohort Consortium (BPC3), we analyzed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age- and cohort-adjusted concordance statistic (AUROCa). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement (IDI) was used to measure improvements in risk prediction.
We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROCa going from 2.7 to 4%). Discriminatory ability for all models varied strongly by hormone receptor status
Discussion and Conclusion
Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
PMCID: PMC3793888  PMID: 22972951
breast cancer; risk prediction; genetic factors; hormone receptor status
22.  Heritability in the genome-wide association era 
Human genetics  2012;131(10):1655-1664.
Heritability, the fraction of phenotypic variation explained by genetic variation, has been estimated for many phenotypes in a range of populations, organisms, and time points. The recent development of efficient genotyping and sequencing technology has led researchers to attempt to identify the genetic variants responsible for the genetic component of phenotype directly via GWAS. The gap between the phenotypic variance explained by GWAS results and those estimated by from classical heritability methods has been termed the “missing heritability problem”. In this work, we examine modern methods for estimating heritability, which use the genotype and sequence data directly. We discuss them in the context of classical heritability methods, the missing heritability problem, and describe their implications for understanding the genetic architecture of complex phentoypes.
PMCID: PMC3432754  PMID: 22821350
heritability; genome-wide association study; prediction; polygenic models; linear mixed models
23.  Challenges and Opportunities in Genome-Wide Environmental Interaction (GWEI) studies 
Human genetics  2012;131(10):1591-1613.
The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies – when the number of environmental or genetic risk factors is relatively small – has been described before.
In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze Genome-Wide Environmental Interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for Genome-Wide Association gene-gene Interaction (GWAI) studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to “joining” two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes.
PMCID: PMC3677711  PMID: 22760307
Genome-wide association studies; gene-environment interaction; post-GWAS analysis; association tests; exploratory methods
24.  Re-Ranking Sequencing Variants in the Post-GWAS Era for Accurate Causal Variant Identification 
PLoS Genetics  2013;9(8):e1003609.
Next generation sequencing has dramatically increased our ability to localize disease-causing variants by providing base-pair level information at costs increasingly feasible for the large sample sizes required to detect complex-trait associations. Yet, identification of causal variants within an established region of association remains a challenge. Counter-intuitively, certain factors that increase power to detect an associated region can decrease power to localize the causal variant. First, combining GWAS with imputation or low coverage sequencing to achieve the large sample sizes required for high power can have the unintended effect of producing differential genotyping error among SNPs. This tends to bias the relative evidence for association toward better genotyped SNPs. Second, re-use of GWAS data for fine-mapping exploits previous findings to ensure genome-wide significance in GWAS-associated regions. However, using GWAS findings to inform fine-mapping analysis can bias evidence away from the causal SNP toward the tag SNP and SNPs in high LD with the tag. Together these factors can reduce power to localize the causal SNP by more than half. Other strategies commonly employed to increase power to detect association, namely increasing sample size and using higher density genotyping arrays, can, in certain common scenarios, actually exacerbate these effects and further decrease power to localize causal variants. We develop a re-ranking procedure that accounts for these adverse effects and substantially improves the accuracy of causal SNP identification, often doubling the probability that the causal SNP is top-ranked. Application to the NCI BPC3 aggressive prostate cancer GWAS with imputation meta-analysis identified a new top SNP at 2 of 3 associated loci and several additional possible causal SNPs at these loci that may have otherwise been overlooked. This method is simple to implement using R scripts provided on the author's website.
Author Summary
As next-generation sequencing (NGS) costs continue to fall and genome-wide association study (GWAS) platform coverage improves, the human genetics community is positioned to identify potentially causal variants. However, current NGS or imputation-based studies of either the whole genome or regions previously identified by GWAS have not yet been very successful in identifying causal variants. A major hurdle is the development of methods to distinguish disease-causing variants from their highly-correlated proxies within an associated region. We show that various common factors, such as differential sequencing or imputation accuracy rates and linkage disequilibrium patterns, with or without GWAS-informed region selection, can substantially decrease the probability of identifying the correct causal SNP, often by more than half. We then describe a novel and easy-to-implement re-ranking procedure that can double the probability that the causal SNP is top-ranked in many settings. Application to the NCI Breast and Prostate Cancer (BPC3) Cohort Consortium aggressive prostate cancer data identified new top SNPs within two associated loci previously established via GWAS, as well as several additional possible causal SNPs that had been previously overlooked.
PMCID: PMC3738448  PMID: 23950724
25.  Analysis of case–control association studies with known risk variants 
Bioinformatics  2012;28(13):1729-1737.
Motivation: The question of how to best use information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each Several Nucleotide Polymorphisms independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertainment, which can induce a correlation structure between candidate variants and known associated variants even if the variants lie on different chromosomes. Here, we propose a new conditioning approach, which is based in part on the classical technique of liability threshold modeling. Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature.
Results: We show via simulation and application to empirical datasets that our approach outperforms both the no conditioning strategy and the standard conditioning strategy, with a properly controlled false-positive rate. Furthermore, in multiple data sets involving diseases of low prevalence, standard conditioning produces a severe drop in test statistics whereas our approach generally performs as well or better than no conditioning. Our approach may substantially improve disease gene discovery for diseases with many known risk variants.
Availability: LTSOFT software is available online
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3381970  PMID: 22556366

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