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Regulation patterns in signaling networks of cancer

Gunnar Schramm, Nandakumar Kannabiran, Rainer König
2010 BMC Systems Biology  
Formation of cellular malignancy results from the disruption of fine tuned signaling homeostasis for proliferation, accompanied by mal-functional signals for differentiation, cell cycle and apoptosis. We wanted to observe central signaling characteristics on a global view of malignant cells which have evolved to selfishness and independence in comparison to their non-malignant counterparts that fulfill well defined tasks in their sample. Results: We investigated the regulation of signaling
more » ... rks with twenty microarray datasets from eleven different tumor types and their corresponding non-malignant tissue samples. Proteins were represented by their coding genes and regulatory distances were defined by correlating the gene-regulation between neighboring proteins in the network (high correlation = small distance). In cancer cells we observed shorter pathways, larger extension of the networks, a lower signaling frequency of central proteins and links and a higher information content of the network. Proteins of high signaling frequency were enriched with cancer mutations. These proteins showed motifs of regulatory integration in normal cells which was disrupted in tumor cells. Conclusion: Our global analysis revealed a distinct formation of signaling-regulation in cancer cells when compared to cells of normal samples. From these cancer-specific regulation patterns novel signaling motifs are proposed.
doi:10.1186/1752-0509-4-162 pmid:21110851 pmcid:PMC3225866 fatcat:hp6epbhr7fcyxdcx7vztyprsm4

A 2-step penalized regression method for family-based next-generation sequencing association studies

Xiuhua Ding, Shaoyong Su, Kannabiran Nandakumar, Xiaoling Wang, David W Fardo
2014 BMC Proceedings  
Large-scale genetic studies are often composed of related participants, and utilizing familial relationships can be cumbersome and computationally challenging. We present an approach to efficiently handle sequencing data from complex pedigrees that incorporates information from rare variants as well as common variants. Our method employs a 2-step procedure that sequentially regresses out correlation from familial relatedness and then uses the resulting phenotypic residuals in a penalized
more » ... ion framework to test for associations with variants within genetic units. The operating characteristics of this approach are detailed using simulation data based on a large, multigenerational cohort.
doi:10.1186/1753-6561-8-s1-s25 pmid:25519315 pmcid:PMC4143756 fatcat:z6l77xbmtffgvbvbr6matbdal4

On family-based genome-wide association studies with large pedigrees: observations and recommendations

David W Fardo, Xue Zhang, Lili Ding, Hua He, Brad Kurowski, Eileen S Alexander, Tesfaye B Mersha, Valentina Pilipenko, Leah Kottyan, Kannabiran Nandakumar, Lisa Martin
2014 BMC Proceedings  
Family based association studies are employed less often than case-control designs in the search for diseasepredisposing genes. The optimal statistical genetic approach for complex pedigrees is unclear when evaluating both common and rare variants. We examined the empirical power and type I error rates of 2 common approaches, the measured genotype approach and family-based association testing, through simulations from a set of multigenerational pedigrees. Overall, these results suggest that
more » ... larger sample sizes will be required for family-based studies and that power was better using MGA compared to FBAT. Taking into account computational time and potential bias, a 2-step strategy is recommended with FBAT followed by MGA.
doi:10.1186/1753-6561-8-s1-s26 pmid:25519377 pmcid:PMC4143718 fatcat:3obmrvi22ncy5bp4dkurotxz7i

Large common deletions associate with mortality at old age

Maris Kuningas, Karol Estrada, Yi-Hsiang Hsu, Kannabiran Nandakumar, André G. Uitterlinden, Kathryn L. Lunetta, Cornelia M. van Duijn, David Karasik, Albert Hofman, Joanne Murabito, Fernando Rivadeneira, Douglas P. Kiel (+1 others)
2011 Human Molecular Genetics  
Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed
more » ... total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (≥500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02 -1.07, P 5 5.82 3 10 25 ] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31 -1.93, P 5 2.87 3 10 26 ) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19 -2.07, P 5 1.53 3 10 23 ) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality.
doi:10.1093/hmg/ddr340 pmid:21835882 pmcid:PMC3188993 fatcat:ycov6fiy4zhk5e3imdlxu5h7l4

Pattern recognition of gene expression data on signalling networks of cancer

Kannabiran Nandakumar
Heidelberg, den Januar 14, 2010 ………… (Kannabiran Nandakumar)  ... 
doi:10.11588/heidok.00010584 fatcat:mnn7ugf4jrggfmbw4okgebgu6a

Targeted sequencing of genome wide significant loci associated with bone mineral density (BMD) reveals significant novel and rare variants: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study

Yi-Hsiang Hsu, Guo Li, Ching-Ti Liu, Jennifer A. Brody, David Karasik, Wen-Chi Chou, Serkalem Demissie, Kannabiran Nandakumar, Yanhua Zhou, Chia-Ho Cheng, Richard Gill, Richard A. Gibbs (+11 others)
2016 Human Molecular Genetics  
Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis. Methods and Results: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n ¼ 925) and Cardiovascular Health Study (n ¼ 366), including 206 women and men with extreme low femoral neck (FN)
more » ... D. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF <1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find proteincoding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5' of MEF2C (P-values < 8x10 À 5 ; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements. Conclusions: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.
doi:10.1093/hmg/ddw289 pmid:27616567 pmcid:PMC5837042 fatcat:bsfiso7lhvcillgu22fotesqsq

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Peter T. Nelson, Steven Estus, Erin L. Abner, Ishita Parikh, Manasi Malik, Janna H. Neltner, Eseosa Ighodaro, Wang-Xia Wang, Bernard R. Wilfred, Li-San Wang, Walter A. Kukull, Kannabiran Nandakumar (+34 others)
2014 Acta Neuropathologica  
doi:10.1007/s00401-014-1282-2 pmid:24770881 pmcid:PMC4113197 fatcat:wgsu5cv4wzhgzjjb7cuydnyv6q

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Ling Oei, Yi-Hsiang Hsu, Unnur Styrkarsdottir, Bert H Eussen, Annelies de Klein, Marjolein J Peters, Bjarni Halldorsson, Ching-Ti Liu, Nerea Alonso, Stephen K Kaptoge, Gudmar Thorleifsson, Göran Hallmans (+56 others)
2013 Journal of Medical Genetics  
Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809
more » ... porotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare ( population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10 −5 ). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis. 122 Oei L, et al.
doi:10.1136/jmedgenet-2013-102064 pmid:24343915 fatcat:ir33aftueresjjcrk43h3obhmy

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi-Hsiang Hsu, Emma L Duncan, Evangelia E Ntzani, Ling Oei, Omar M E Albagha, Najaf Amin, John P Kemp, Daniel L Koller, Guo Li (+169 others)
2012 Nature Genetics  
doi:10.1038/ng.2249 pmid:22504420 pmcid:PMC3338864 fatcat:ajfqfcseo5hmjmwfbztf5rqsdm

Analyzing combinatorial regulation of transcription in mammalian cells

Anna-Lena Kranz
Nandakumar, and Matthias Eidel, for the warm atmosphere and many (not always science related) discussions.  ...  uniformlydistributed-BS A big thank you goes to former and current members of the Network modeling group, specifically Gunnar Schramm, Tobias Bauer, Richa Batra, Kitiporn Plaimas, Apichat Suratanee, Kannabiran  ... 
doi:10.11588/heidok.00011769 fatcat:bg3v7uek2vfltpavqama7icp4e