| 1. |
- Figueroa, Jonine D., et al.
(författare)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Tidskriftsartikel (refereegranskat)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 2. |
- Laskar, Ruhina S, et al.
(författare)
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Sex specific associations in genome wide association analysis of renal cell carcinoma.
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:10, s. 1589-1598
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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| 3. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Berndt, Sonja I., et al.
(författare)
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Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
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| 6. |
- Gaudet, Mia M., et al.
(författare)
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Anthropometry and head and neck cancer : a pooled analysis of cohort data
- 2015
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 44:2, s. 673-681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies. Methods: We pooled data from 1 941 300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status. Results: Greater waist circumference (per 5cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers. Conclusions: Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
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| 7. |
- Kitahara, Cari M., et al.
(författare)
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Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype : Pooled Analysis of 22 Prospective Studies
- 2016
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Ingår i: Thyroid. - : MARY ANN LIEBERT, INC. - 1050-7256 .- 1557-9077. ; 26:2, s. 306-318
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Tidskriftsartikel (refereegranskat)abstract
- Background: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. Methods: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. Results: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5cm)=1.07 [1.04-1.10], BMI (per 5kg/m(2))=1.06 [1.02-1.10], waist circumference (per 5cm)=1.03 [1.01-1.05], young-adult BMI (per 5kg/m(2))=1.13 [1.02-1.25], and adulthood BMI gain (per 5kg/m(2))=1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p=0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. Conclusion: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.
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| 8. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 9. |
- Machiela, Mitchell J., et al.
(författare)
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Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:8, s. 1663-1676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
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| 10. |
- Zhang, Mingfeng, et al.
(författare)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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