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Bivariate Genome-Wide Association Analyses of Femoral Neck Bone Geometry and Appendicular Lean Mass  [PDF]
Lu Sun, Li-Jun Tan, Shu-Feng Lei, Xiang-Ding Chen, Xi Li, Rong Pan, Fang Yin, Quan-Wei Liu, Xiao-Feng Yan, Christopher J. Papasian, Hong-Wen Deng
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027325
Abstract: Objective Femoral neck geometric parameters (FNGPs), such as periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are highly genetically correlated with body lean mass. However, the specific SNPs/genes shared by these phenotypes are largely unknown. Methods To identify the specific SNPs/genes shared between FNGPs and appendicular lean mass (ALM), we performed an initial bivariate genome-wide association study (GWAS) by scanning ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) and a follow-up replicate study in 2,286 unrelated US Caucasians. Results We identified 13 interesting SNPs that may be important for both FNGPs and ALM. Two SNPs, rs681900 located in the HK2 (hexokinase 2) gene and rs11859916 in the UMOD (uromodulin) gene, were bivariately associated with FNGPs and ALM (p = 7.58×10?6 for ALM-BR and p = 2.93×10?6 for ALM-W, respectively). The associations were then replicated in Caucasians, with corresponding p values of 0.024 for rs681900 and 0.047 for rs11859916. Meta-analyses yielded combined p values of 3.05×10?6 and 2.31×10?6 for rs681900 and rs11859916, respectively. Our findings are consistent with previous biological studies that implicated HK2 and UMOD in both FNGPs and ALM. Our study also identified a group of 11 contiguous SNPs, which spanned a region of ~130 kb, were bivariately associated with FNGPs and ALM, with p values ranging from 3.06×10?7 to 4.60×10?6 for ALM-BR. The region contained two neighboring miRNA coding genes, MIR873 (MicroRNA873) and MIR876 (MicroRNA876). Conclusion Our study implicated HK2, UMOD, MIR873 and MIR876, as pleiotropic genes underlying variation of both FNGPs and ALM, thus suggesting their important functional roles in co-regulating both FNGPs and ALM.
Copy number variations (CNVs) identified in Korean individuals
Tae-Wook Kang, Yeo-Jin Jeon, Eunsu Jang, Hee-Jin Kim, Jeong-Hwan Kim, Jong-Lyul Park, Siwoo Lee, Yong Kim, Jong Kim, Seon-Young Kim
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-492
Abstract: We identified 65 copy number variation regions (CNVRs) in 116 normal Korean individuals by analyzing Affymetrix 250 K Nsp whole-genome SNP data. Ten of these CNVRs were novel and not present in the Database of Genomic Variants (DGV). To increase the specificity of CNV detection, three algorithms, CNAG, dChip and GEMCA, were applied to the data set, and only those regions recognized at least by two algorithms were identified as CNVs. Most CNVRs identified in the Korean population were rare (<1%), occurring just once among the 116 individuals. When CNVs from the Korean population were compared with CNVs from the three HapMap ethnic groups, African, European, and Asian; our Korean population showed the highest degree of overlap with the Asian population, as expected. However, the overlap was less than 40%, implying that more CNVs remain to be discovered from the Asian population as well as from other populations. Genes in the novel CNVRs from the Korean population were enriched for genes involved in regulation and development processes.CNVs are recently-recognized structural variations among individuals, and more CNVs need to be identified from diverse populations. Until now, CNVs from Asian populations have been studied less than those from European or American populations. In this regard, our study of CNVs from the Korean population will contribute to the full cataloguing of structural variation among diverse human populations.Understanding variations in the human genome is the key to unraveling the phenotypic diversity among individuals and understanding various human diseases. Genomic variations exist at various levels, from differences in single nucleotides to microscopic chromosome-level variation [1]. Copy number variations (CNVs), a new type of genomic variation that has recently received considerable attention, are deletions, insertions, duplications, and more complex variations ranging from 1 kb to submicroscopic sizes [1-4]. Recent advances in array technolo
Copy Number Variation across European Populations  [PDF]
Wanting Chen,Caroline Hayward,Alan F. Wright,Andrew A. Hicks,Veronique Vitart,Sara Knott,Sarah H. Wild,Peter P. Pramstaller,James F. Wilson,Igor Rudan,David J. Porteous
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0023087
Abstract: Genome analysis provides a powerful approach to test for evidence of genetic variation within and between geographical regions and local populations. Copy number variants which comprise insertions, deletions and duplications of genomic sequence provide one such convenient and informative source. Here, we investigate copy number variants from genome wide scans of single nucleotide polymorphisms in three European population isolates, the island of Vis in Croatia, the islands of Orkney in Scotland and the South Tyrol in Italy. We show that whereas the overall copy number variant frequencies are similar between populations, their distribution is highly specific to the population of origin, a finding which is supported by evidence for increased kinship correlation for specific copy number variants within populations.
Exploring correlations among copy number variants  [PDF]
Joseph Abraham, Thomas LaFramboise
Open Journal of Genetics (OJGen) , 2012, DOI: 10.4236/ojgen.2012.23018
Abstract: There have been a great many recent studies investigating the extent of Copy Number Variation in the genomes of various species such as human, cattle, dogs and many others. The results from these studies indicate that the extent of the Copy Number Variation in the genome is considerable, and that in humans and in cattle, frequencies of different Copy Number Variants may differ in different breeds/ethnicities. This is not entirely unexpected as allele frequencies of certain loci vary with different breeds/ ethnicities/species and many known Copy Number Variants behave similarly to ordinary markers as regards Mendelian segregation. It is also well known in many instances, species/breeds/ethnicities show variation not only in marker allele frequencies, but also in the extent of Linkage Disequilibrium between markers. Thus it is worth investigating the extent of association between Copy Number Variants in different populations. In this paper we will investigate the extent of correlations between selected Copy Number Variants in different human populations and show that statistically significant correlations exist and are strongly population dependent.
Relationship between Dual-Energy X-Ray Absorptiometry-Derived Appendicular Lean Tissue Mass and Total Body Skeletal Muscle Mass Estimated by Ultrasound  [PDF]
Takashi Abe, Nicole C. Dabbs, Vinayak K. Nahar, M. Allison Ford, Martha A. Bass, Mark Loftin
International Journal of Clinical Medicine (IJCM) , 2013, DOI: 10.4236/ijcm.2013.46049

Dual-energy X-ray absorptiometry (DXA) is an attractive method for evaluating sarcopenia, age-related loss of skeletal muscle mass and function, using appendicular lean tissue (aLT) mass for criteria of diagnosis, although minimal radiation is exposed. Skeletal muscle (SM) mass can be estimated by using ultrasound-measured muscle thickness (MTH). However, the association between these two methods is unclear. To examine the relationship between DXA-derived aLT mass and total body SM mass estimated by ultrasound, thirty-six healthy adults (18 men and 18 women) aged 19 - 65 years participated in this study. Ultrasound-measured muscle thickness was used to estimate the total SM mass. DXA was used to estimate whole body and regional body composition, and aLT mass was considered equivalent to the sum of lean tissue in both the right and left arms and legs. Total SM mass (26.3 ± 4.4 kg for men and 15.7 ± 2.6 kg for women) estimated by ultrasound was similar to DXA-estimated aLT mass (24.5 ± 3.8 kg for men and 15.7 ± 2.7 kg for women). There was a strong correlation between DXA-measured aLT mass and total SM mass estimated by ultrasound in men (r = 0.927, n = 18) and women (r = 0.931, n = 18) as well as overall sample (r = 0.975, n = 36). The ratio of total SM mass to aLT mass was 1.07 for men and 1.00 for women. These results suggest that DXA-derived aLT mass can be accurately predicted from ultrasound estimated total SM mass, although the predicted value may

Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans  [PDF]
Daniel R. Schrider equal contributor ,Fabio C. P. Navarro equal contributor ,Pedro A. F. Galante,Raphael B. Parmigiani,Anamaria A. Camargo,Matthew W. Hahn,Sandro J. de Souza
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003242
Abstract: The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance.
The Professional Medical Journal , 2010,
Abstract: Introduction: Appendicular mass is a common complication of acute appendicitis. The traditional treatment of this is conservative followed by delayed appendectomy. But now with advancement in all the fields of medicine early surgical exploration of the appendicular mass can be done with satisfactory results. Aims and objectives: A comparison of conservative treatment versus early surgical exploration of appendicular mass. Study Design: Experimental study. Material and Method: Two years study from December 2003 to November 2005 at district headquarters hospital Khanewal. Total 60 patients, both males and females between 12 to 65 years of age with symptoms and signs consistent with appendicular mass were included. They were randomly divided into group I (Early exploration) and group II(Conservative treatment) each containing 30 patients. A comparison of outcome between two groups was done statistically by applying studentChi-square test. Results: There was a peak incidence of acute appendicitis in Second and third decades of life. Male to female ratio was 2:1.More than 90% of patients had history of shifting of abdominal pain. 100% of the patients had inflamed appendix to variable extent onexploration. The complications in the form of adhesive intestinal obstruction; failure of treatment; lost follow up; misdiagnosis and re admission were less in group I. There was a significant less duration of hospital stay in group I as compared to Group II. The observations and outcome in this study are almost comparable and correspond with other studies done in this regard. Conclusion: Early surgical exploration of appendicular mass is safe and cost effective.
Genome-Wide Association Study of Copy Number Variants Suggests LTBP1 and FGD4 Are Important for Alcohol Drinking  [PDF]
Yu-Fang Pei, Lei Zhang, Tie-Lin Yang, Yingying Han, Rong Hai, Shu Ran, Qing Tian, Hui Shen, Jian Li, Xue-Zhen Zhu, Xingguang Luo, Hong-Wen Deng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030860
Abstract: Alcohol dependence (AD) is a complex disorder characterized by psychiatric and physiological dependence on alcohol. AD is reflected by regular alcohol drinking, which is highly inheritable. In this study, to identify susceptibility genes associated with alcohol drinking, we performed a genome-wide association study of copy number variants (CNVs) in 2,286 Caucasian subjects with Affymetrix SNP6.0 genotyping array. We replicated our findings in 1,627 Chinese subjects with the same genotyping array. We identified two CNVs, CNV207 (combined p-value 1.91E-03) and CNV1836 (combined p-value 3.05E-03) that were associated with alcohol drinking. CNV207 and CNV1836 are located at the downstream of genes LTBP1 (870 kb) and FGD4 (400 kb), respectively. LTBP1, by interacting TGFB1, may down-regulate enzymes directly participating in alcohol metabolism. FGD4 plays a role in clustering and trafficking GABAA receptor and subsequently influence alcohol drinking through activating CDC42. Our results provide suggestive evidence that the newly identified CNV regions and relevant genes may contribute to the genetic mechanism of alcohol dependence.
A Computational Framework Discovers New Copy Number Variants with Functional Importance  [PDF]
Samprit Banerjee,Derek Oldridge,Maria Poptsova,Wasay M. Hussain,Dimple Chakravarty,Francesca Demichelis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017539
Abstract: Structural variants which cause changes in copy numbers constitute an important component of genomic variability. They account for 0.7% of genomic differences in two individual genomes, of which copy number variants (CNVs) are the largest component. A recent population-based CNV study revealed the need of better characterization of CNVs, especially the small ones (<500 bp).We propose a three step computational framework (Identification of germline Changes in Copy Number or IgC2N) to discover and genotype germline CNVs. First, we detect candidate CNV loci by combining information across multiple samples without imposing restrictions to the number of coverage markers or to the variant size. Secondly, we fine tune the detection of rare variants and infer the putative copy number classes for each locus. Last, for each variant we combine the relative distance between consecutive copy number classes with genetic information in a novel attempt to estimate the reference model bias. This computational approach is applied to genome-wide data from 1250 HapMap individuals. Novel variants were discovered and characterized in terms of size, minor allele frequency, type of polymorphism (gains, losses or both), and mechanism of formation. Using data generated for a subset of individuals by a 42 million marker platform, we validated the majority of the variants with the highest validation rate (66.7%) was for variants of size larger than 1 kb. Finally, we queried transcriptomic data from 129 individuals determined by RNA-sequencing as further validation and to assess the functional role of the new variants. We investigated the possible enrichment for variant's regulatory effect and found that smaller variants (<1 Kb) are more likely to regulate gene transcript than larger variants (p-value = 2.04e-08). Our results support the validity of the computational framework to detect novel variants relevant to disease susceptibility studies and provide evidence of the importance of genetic variants in regulatory network studies.
Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence  [PDF]
Yadav Sapkota, Sunita Ghosh, Raymond Lai, Bradley P. Coe, Carol E. Cass, Yutaka Yasui, John R. Mackey, Sambasivarao Damaraju
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053850
Abstract: Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60–21.78) and 8.60 years (range = 3.08–13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01×10?5) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10?5) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.
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