7 research outputs found
Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations
All authors: Olga Y. Gorlova ,
Yafang Li,
Ivan Gorlov,
Jun Ying,
Wei V. Chen,
Shervin Assassi,
John D. Reveille,
Frank C. Arnett,
Xiaodong Zhou,
Lara Bossini-Castillo,
Elena Lopez-Isac,
Marialbert Acosta-Herrera,
Peter K. Gregersen,
Annette T. Lee,
Virginia D. Steen,
Barri J. Fessler,
Dinesh Khanna,
Elena Schiopu,
Richard M. Silver,
Jerry A. Molitor,
Daniel E. Furst,
Suzanne Kafaja,
Robert W. Simms,
Robert A. Lafyatis,
Patricia Carreira,
Carmen Pilar Simeon,
Ivan Castellvi,
Emma Beltran,
Norberto Ortego,
Christopher I. Amos,
Javier Martin,
Maureen D. Mayes.Data Availability Statement: Genetic data is
available from dbGaP repository (https://www.ncbi.
nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_
id=phs000357.v1.p1).Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.Funding was provided to MDM by the National Institutes of Health (NIH) the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS https://www.niams.nih.gov/) Centers of Research Translation (CORT) P50-AR054144, NIH grant N01-AR-02251 and R01-AR-055258, and the Department of Defense (DD) Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) W81XWH-07-1-011 and WX81XWH-13-1-0452 for the collection, analysis and interpretation of the data
Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies
<div><p>Background</p><p>Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype.</p><p>Methods</p><p>To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at <i>P</i><5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls).</p><p>Results</p><p>Multiple correlated SNPs in intron 1 of the <i>ROBO1</i> gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, <i>P</i><sub>discovery</sub> = 1.2E-04; rs7429100, <i>P</i><sub>replication</sub> = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (<i>P</i> = 1.84E-06).</p><p>Conclusion</p><p>The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of <i>ROBO1</i>, a potential tumor suppressor gene, merits further investigation.</p></div
Descriptive characteristics of participating genome-wide association studies in the Discovery and Replication analyses.
<p>Descriptive characteristics of participating genome-wide association studies in the Discovery and Replication analyses.</p
Association results for the Discovery, Replication and combined Meta-analysis, for SNPs with <i>P</i><0.05 in the Replication data, by chromosome.
<p>Association results for the Discovery, Replication and combined Meta-analysis, for SNPs with <i>P</i><0.05 in the Replication data, by chromosome.</p
Genes most significant (at p<10<sup>−3</sup>) in African Americans in the gene-level analysis and the results for these genes in Whites, based on ImmunoChip.
<p>Genes most significant (at p<10<sup>−3</sup>) in African Americans in the gene-level analysis and the results for these genes in Whites, based on ImmunoChip.</p
Results of the gene-level analyses for known genes associated with risk of SSc in Whites and African Americans, based on ImmunoChip.
<p>Results of the gene-level analyses for known genes associated with risk of SSc in Whites and African Americans, based on ImmunoChip.</p
Comparison of novel candidate genes (at p<4.35x10<sup>-6</sup> indicated in bold) and suggestive genes (4.35x10<sup>-6</sup>−5) detected in Whites to the corresponding statistics in African Americans in the gene level analysis, based on ImmunoChip.
<p>Comparison of novel candidate genes (at p<4.35x10<sup>-6</sup> indicated in bold) and suggestive genes (4.35x10<sup>-6</sup>−5) detected in Whites to the corresponding statistics in African Americans in the gene level analysis, based on ImmunoChip.</p