| 1. |
- Deng, Min, et al.
(författare)
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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis
- 2013
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 45:6, s. 697-
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.
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| 2. |
- Low, Yen Ling, et al.
(författare)
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Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:7, s. e1001012-
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Tidskriftsartikel (refereegranskat)abstract
- Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (rho(global) = 0.034) and endometrial (rho(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (rho(global) = 0.008) and endometrial cancer (rho(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (rho(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (rho(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
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| 3. |
- Smedby, Karin E., et al.
(författare)
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GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:4, s. e1001378-
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Tidskriftsartikel (refereegranskat)abstract
- Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, P-combined= 2x10(-21)) located 962 bp away from rs10484561 (r(2)< 0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012: ORadjusted = 0.70, P-adjusted= 4x10(-12); rs10484561: ORadjusted = 1.64, P-adjusted= 5x10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, P-combined = 1.4x10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
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| 4. |
- Baecklund, Fredrik, et al.
(författare)
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A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival
- 2014
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15, s. 113-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. Methods: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of similar to 300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. Results: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0x10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24x10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. Conclusions: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
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| 5. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 6. |
- Conde, Lucia, et al.
(författare)
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Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:8, s. 661-664
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).
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| 7. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 8. |
- Foo, Jia Nee, et al.
(författare)
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Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk
- 2013
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 93:1, s. 167-172
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Tidskriftsartikel (refereegranskat)abstract
- Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 x 10(-15)). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 x 10(-14)). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.
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| 9. |
- Ge, Yue, et al.
(författare)
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Environmental OMICS: Current Status and Future Directions
- 2013
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Ingår i: JOURNAL OF INTEGRATED OMICS. - : Proteomass Scientific Society. - 2182-0287. ; 3:2, s. 75-87
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Tidskriftsartikel (refereegranskat)abstract
- Applications of OMICS to high throughput studies of changes of genes, RNAs, proteins, metabolites, and their associated functionsin cells or organisms exposed to environmental chemicals has led to the emergence of a very active research field: environmental OMICS.This developing field holds an important key for improving the scientific basis for understanding the potential impacts of environmentalchemicals on both health and the environment. Here we describe the state of environmental OMICS with an emphasis on its recent accomplishmentsand its problems and potential solutions to facilitate the incorporation of OMICS into mainstream environmental and healthresearch.Data sources: We reviewed relevant and recently published studies on the applicability and usefulness of OMICS technologies to the identificationof toxicity pathways, mechanisms, and biomarkers of environmental chemicals for environmental and health risk monitoring andassessment, including recent presentations and discussions on these issues at The First International Conference on Environmental OMICS(ICEO), held in Guangzhou, China during November 8-12, 2011. This paper summarizes our review.Synthesis: Environmental OMICS aims to take advantage of powerful genomics, transcriptomics, proteomics, and metabolomics tools toidentify novel toxicity pathways/signatures/biomarkers so as to better understand toxicity mechanisms/modes of action, to identify/categorize/prioritize/screen environmental chemicals, and to monitor and predict the risks associated with exposure to environmental chemicalson human health and the environment. To improve the field, some lessons learned from previous studies need to be summarized, aresearch agenda and guidelines for future studies need to be established, and a focus for the field needs to be developed.Conclusions: OMICS technologies for identification of RNA, protein, and metabolic profiles and endpoints have already significantly improvedour understanding of how environmental chemicals affect our ecosystem and human health. OMICS breakthroughs are empoweringthe fields of environmental toxicology, chemical toxicity characterization, and health risk assessment. However, environmental OMICS is stillin the data generation and collection stage. Important data gaps in linking and/or integrating toxicity data with OMICS endpoints/profilesneed to be filled to enable understanding of the potential impacts of chemicals on human health and the environment. It is expected thatfuture environmental OMICS will focus more on real environmental issues and challenges such as the characterization of chemical mixturetoxicity, the identification of environmental and health biomarkers, and the development of innovative environmental OMICS approachesand assays. These innovative approaches and assays will inform chemical toxicity testing and prediction, ecological and health risk monitoringand assessment, and natural resource utilization in ways that maintain human health and protects the environment in a sustainable manner.
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| 10. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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