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ABSTRACT: This report describes a three generation family with late onset bilateral sensorineural hearing impairment (BLSNHI) and tinnitus in which a novel mutation in the COCH gene was identified after a genome-wide linkage approach. The COCH gene is one of the few genes clinically examined when investigating the etiology of autosomal dominant late onset hearing impairment. Initially mutations in the COCH gene were only reported in exons 4 and 5, coding for the LCCL protein domain. More recently, additional mutations have been identified in exon 12, the only mutations identified outside of the LCCL domain. Currently clinical genetic testing for the COCH gene primarily focuses on identifying mutations in these three exons. In this study, we identify a novel mutation in the COCH gene in exon 11, which, like the exon 12 mutations, falls within the vWFA2 protein domain. This finding reinforces the need for clinical genetic screening of the COCH gene to be expanded beyond the current limited exon screening, as there is now more evidence to support that mutations in other areas of this gene are also causative of a similar form of late onset BLSNHI.
American journal of otolaryngology 01/2013; · 0.77 Impact Factor
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ABSTRACT: BACKGROUND & AIMS: Biliary atresia (BA) is a progressive fibro-inflammatory disorder of infants involving the extra- and intra-hepatic biliary tree. Its etiology is unclear, but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. Biliary atresia occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. METHODS: We searched for copy number variants that were increased among patients with BA (n=61) compared to healthy individuals (controls; n=5,088). After identifying a candidate gene, we investigated expression patterns of orthologs in zebrafish liver, and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. RESULTS: We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of 1 copy of GPC1, which encodes glypican 1-a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes, compared with samples from controls. CONCLUSIONS: Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA.
Gastroenterology 01/2013; · 11.68 Impact Factor
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Mario Capasso,
Sharon Diskin,
Francesca Totaro,
Luca Longo,
Marilena De Mariano,
Roberta Russo,
Flora Cimmino,
Hakon Hakonarson,
Gian Paolo Tonini, Marcella Devoto,
John M Maris,
Achille Iolascon
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ABSTRACT: Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1, and LIN28B by genome-wide association (GWA) studies including European American (EA) individuals. To validate and comprehensively evaluate the impact of the identified NB variants on disease risk and phenotype, we analyzed 16 single nucleotide polymorphisms (SNPs) in an Italian population (370 cases and 809 controls). We assessed their regulatory activity on gene expression in lymphoblastoid (LCLs) and NB cell lines. We evaluated the cumulative effect of the independent loci on NB risk and high-risk phenotype development in Italian and EAs (1627 cases and 2575 controls) populations. All NB susceptibility genes replicated in the Italian dataset except for DDX4 and IL31RA, and the most significant SNP was rs6435862 in BARD1 (P=8.4x10(-15)). BARD1 showed an additional and independent SNP association (rs7585356). This variant influenced BARD1 mRNA expression in LCLs and NB cell lines. No evidence of epistasis among the NB-associated variants was detected while a cumulative effect of risk variants on NB risk (EAs: P(trend)=6.9x10(-30), Italians: P(trend)=8.55x10(-13)) and development of high-risk phenotype (EAs: P(trend)=6.9x10(-13), Italians: P(trend)=2.2x10(-1)) was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWA studies contribute to NB susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NB risk. This study shows that even in the absence of interaction the combination of several low-penetrance alleles has potential to distinguish sub-groups of patients at different risks of developing NB.
Carcinogenesis 12/2012; · 5.70 Impact Factor
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Sharon J Diskin,
Mario Capasso,
Robert W Schnepp,
Kristina A Cole,
Edward F Attiyeh,
Cuiping Hou,
Maura Diamond,
Erica L Carpenter,
Cynthia Winter,
Hanna Lee,
Jayanti Jagannathan,
Valeria Latorre,
Achille Iolascon,
Hakon Hakonarson, Marcella Devoto,
John M Maris
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Mario Capasso, Marcella Devoto,
Cuiping Hou,
Shahab Asgharzadeh,
Joseph T Glessner,
Edward F Attiyeh,
Yael P Mosse,
Cecilia Kim,
Sharon J Diskin,
Kristina A Cole, [......],
Maria Garris,
Carmel McConville,
Wendy B London,
Robert C Seeger,
Struan F A Grant,
Hongzhe Li,
Nazneen Rahman,
Eric Rappaport,
Hakon Hakonarson,
John M Maris
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Sharon J Diskin,
Mario Capasso,
Robert W Schnepp,
Kristina A Cole,
Edward F Attiyeh,
Cuiping Hou,
Maura Diamond,
Erica L Carpenter,
Cynthia Winter,
Hanna Lee,
Jayanti Jagannathan,
Valeria Latorre,
Achille Iolascon,
Hakon Hakonarson, Marcella Devoto,
John M Maris
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ABSTRACT: Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P = 2.7 × 10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P = 1.2 × 10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P = 0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
Nature Genetics 09/2012; 44(10):1126-30. · 35.53 Impact Factor
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ABSTRACT: Neuroblastoma is an often fatal pediatric cancer more frequent in European-American than African-American children. African-American children, however, are at higher risk for the more severe form of neuroblastoma and have worse overall survival than European-American children. Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNP) associated to neuroblastoma in children of European descent. Knowledge of their association to neuroblastoma in African-American children is still lacking.
We genotyped and imputed SNPs located in three gene regions reported to be associated to neuroblastoma in children of European descent, and tested them for association in 390 African-American patients with neuroblastoma compared with 2,500 healthy, ethnically matched controls.
SNPs in the BARD1 gene region show a similar pattern of association to neuroblastoma in African-American and European-American children. The more restricted extent of linkage disequilibrium in the African-American population suggests a smaller candidate region for the putative causal variants than previously reported. Limited association was observed at the other two gene regions tested, including LMO1 in 11p15 and FLJ22536 in 6p22.
Common BARD1 SNPs affect risk of neuroblastoma in African-Americans. The role of other SNPs associated to neuroblastoma in children of European descent could not be confirmed, possibly due to different patterns of linkage disequilibrium or limited statistical power to detect association to variants with small effect on disease risk. Extension of GWAS to populations of African descent is important to confirm their results and validity beyond the European populations and can help to refine the location of the putative causal variants.
Cancer Epidemiology Biomarkers & Prevention 02/2012; 21(4):658-63. · 4.12 Impact Factor
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Kristopher R Bosse,
Sharon J Diskin,
Kristina A Cole,
Andrew C Wood,
Robert W Schnepp,
Geoffrey Norris,
Le B Nguyen,
Jayanti Jagannathan,
Michael Laquaglia,
Cynthia Winter, [......],
Yongqiang Zhang,
Shahab Asgharzadeh,
Robert C Seeger,
Mario Capasso,
Bruce R Pawel, Marcella Devoto,
Hakon Hakonarson,
Eric F Rappaport,
Irmgard Irminger-Finger,
John M Maris
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ABSTRACT: The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1β. In neuroblastoma cells, silencing of BARD1β showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1β was sufficient for neoplastic transformation. BARD1β stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1β as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1β with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma.
Cancer Research 02/2012; 72(8):2068-78. · 7.86 Impact Factor
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ABSTRACT: The clinical and hematologic features of β-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of β-thalassemia as assessed by the patients' age at first transfusion.
We studied the effect of seven loci in a cohort of 316 Sardinian patients with β(0)-thalassemia. In addition to characterizing the β-globin gene mutations, α-globin gene defects and HBG2:g.-158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion.
According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell's concordance index=0.72; Cox & Snell R(2)=0.394) and demonstrated that most of the model's discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.-158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R(2)=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population.
This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of β(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.
Haematologica 01/2012; 97(7):989-93. · 6.42 Impact Factor
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Josephine Elia,
Joseph T Glessner,
Kai Wang,
Nagahide Takahashi,
Corina J Shtir,
Dexter Hadley,
Patrick M A Sleiman,
Haitao Zhang,
Cecilia E Kim,
Reid Robison, [......],
Philip Shaw, Marcella Devoto,
Peter S White,
Struan F A Grant,
Joseph D Buxbaum,
Judith L Rapoport,
Nigel M Williams,
Stanley F Nelson,
Stephen V Faraone,
Hakon Hakonarson
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ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
Nature Genetics 12/2011; 44(1):78-84. · 35.53 Impact Factor
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Le B Nguyen,
Sharon J Diskin,
Mario Capasso,
Kai Wang,
Maura A Diamond,
Joseph Glessner,
Cecilia Kim,
Edward F Attiyeh,
Yael P Mosse,
Kristina Cole,
Achille Iolascon, Marcella Devoto,
Hakon Hakonarson,
Hongzhe K Li,
John M Maris
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ABSTRACT: Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07 × 10⁻⁶), DDX4 and IL31RA both at 5q11.2 (P = 2.94 × 10⁻⁶ and 6.54 × 10⁻⁷ respectively), and HSD17B12 at 11p11.2 (P = 4.20 × 10⁻⁷) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma.
PLoS Genetics 03/2011; 7(3):e1002026. · 8.69 Impact Factor
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Kai Wang,
Sharon J Diskin,
Haitao Zhang,
Edward F Attiyeh,
Cynthia Winter,
Cuiping Hou,
Robert W Schnepp,
Maura Diamond,
Kristopher Bosse,
Patrick A Mayes, [......],
Yael P Mosse,
Kristina A Cole,
Hongzhe Li, Marcella Devoto,
Patrick W McGrady,
Wendy B London,
Mario Capasso,
Nazneen Rahman,
Hakon Hakonarson,
John M Maris
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ABSTRACT: Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.
Nature 01/2011; 469(7329):216-20. · 36.28 Impact Factor
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ABSTRACT: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB.
To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations.
The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance.
This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases.
Human Heredity 01/2011; 71(2):135-9. · 1.79 Impact Factor
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ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder influenced by genetic factors. Several chromosomal regions with potential linkage and candidate genes associations have been reported, but findings are often inconsistent and non-replicated. The few genome-wide association studies (GWAS) carried out so far differ for study design and phenotypes analyzed, and did not detect any association significant at the genome-wide level. In the present study we examined the top SNPs reported in the GWAS by Neale et al. 2008 in an independent cohort. Although our sample size is smaller (415 trios vs. 909), the power was sufficient to confirm the role of candidate markers in ADHD if a true association exists. Two out of 36 top SNPs were significant at alpha = 0.05 in our sample, although none was still significant after correction for multiple tests. These two SNPs are both located in genes coding for as yet uncharacterized proteins expressed in the cerebellum, XKR4 in 8q12.1, and FAM190A in 4q22.1. Three other FAM190A SNPs have TDT P-values of <10(-5) in our sample, a level of significance only reached by a total of five SNPs in our genome-wide data. While these findings could be due to chance, we cannot exclude that these markers are indeed associated to disease risk. Remarkably, brain imaging studies have shown reduction of the posterior inferior cerebellar lobules volume of ADHD boys and girls compared to controls, persistent with age and not present in unaffected siblings, suggesting that the cerebellum may be directly related to pathophysiology of ADHD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2010; 153B(6):1127-33. · 3.70 Impact Factor
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Patrick M A Sleiman,
James Flory,
Marcin Imielinski,
Jonathan P Bradfield,
Kiran Annaiah,
Saffron A G Willis-Owen,
Kai Wang,
Nicholas M Rafaels,
Sven Michel,
Klaus Bonnelykke, [......],
Michael Kabesch,
Miriam F Moffatt,
Michael M Grunstein,
Kathleen C Barnes, Marcella Devoto,
Mark Magnusson,
Hongzhe Li,
Struan F A Grant,
Hans Bisgaard,
Hakon Hakonarson
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ABSTRACT: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.
We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls.
In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected].
We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.
New England Journal of Medicine 01/2010; 362(1):36-44. · 53.30 Impact Factor
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ABSTRACT: Developmental dysplasia of the hip (DDH) is a disabling condition that, depending on geography, can afflict between 20% and 80% of patients with end-stage arthritis of the hip. Despite its prevalence, the etiology of this disease remains unknown. DDH is a complex disorder with both environmental and genetic causes. Based on the literature the candidate genes for the disease are HOXB9, collagen type I alpha1, and DLX 3. The purpose of our study was to map and characterize the gene or genes responsible for this disorder by family linkage analysis. We recruited one 18-member, multigeneration affected family to provide cheek swabs and blood samples for isolation of DNA. Amplified DNA underwent a total genome scan using GeneChip Mapping 250 K Assay (Affymetrix, Santa Clara, CA). We observed only one region with a LOD score greater than 1.5: a 4 Mb region on chromosome 17q21.32, yielding a LOD score of 1.82. While a LOD score of 1.82 does not meet the accepted standard for linkage we interpret these data as suggesting the responsible gene could be linked to this region, which includes a cluster of homeobox genes (HOX genes) that are part of the developmental regulatory system providing cells with specific positional identities along the developing joint and spine. Discovering the genetic basis of the disease would be an important step in understanding the etiology of this disabling condition.
Clinical Orthopaedics and Related Research 09/2009; 468(2):337-44. · 2.53 Impact Factor
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Sharon J Diskin,
Cuiping Hou,
Joseph T Glessner,
Edward F Attiyeh,
Marci Laudenslager,
Kristopher Bosse,
Kristina Cole,
Yaël P Mossé,
Andrew Wood,
Jill E Lynch, [......],
Alexandra I F Blakemore,
Wendy B London,
Tamim H Shaikh,
Jonathan Bradfield,
Struan F A Grant,
Hongzhe Li, Marcella Devoto,
Eric R Rappaport,
Hakon Hakonarson,
John M Maris
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ABSTRACT: Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.
Nature 07/2009; 459(7249):987-91. · 36.28 Impact Factor
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Mario Capasso, Marcella Devoto,
Cuiping Hou,
Shahab Asgharzadeh,
Joseph T Glessner,
Edward F Attiyeh,
Yael P Mosse,
Cecilia Kim,
Sharon J Diskin,
Kristina A Cole, [......],
Maria Garris,
Carmel McConville,
Wendy B London,
Robert C Seeger,
Struan F A Grant,
Hongzhe Li,
Nazneen Rahman,
Eric Rappaport,
Hakon Hakonarson,
John M Maris
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ABSTRACT: We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (P(allelic) = 2.35 x 10(-9)-2.25 x 10(-8)). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (P(allelic) = 7.90 x 10(-7)-2.77 x 10(-4)). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma.
Nature Genetics 06/2009; 41(6):718-23. · 35.53 Impact Factor
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Josephine Elia,
Toshinobu Takeda,
Rachel Deberardinis,
Judy Burke,
Jennifer Accardo,
Paul J Ambrosini,
Nathan J Blum,
Lawrence W Brown,
Francesca Lantieri,
Wade Berrettini, Marcella Devoto,
Hakon Hakonarson
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ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear.
Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored.
The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis.
Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.
The Journal of pediatrics 06/2009; 155(2):239-44.e5. · 4.02 Impact Factor
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ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common developmental disorder. Although a few confirmed associations have emerged from candidate gene studies, these have shown the same limitations that have become evident in the study of other complex diseases, often with inconsistent and nonreplicated results across different studies.
In this report, 27 ADHD candidate genes were explored in greater depth using high-density tag single nucleotide polymorphism (SNP) genotyping. Association with 557 SNPs was tested using the transmission disequilibrium test in 270 nuclear pedigrees selected from an ongoing ADHD genetic study that includes all disease subtypes.
SNPs in seven genes including SLC1A3, SLC6A3, HTR4, ADRA1A, HTR2A, SNAP25, and COMT showed a nominal level of association with ADHD (P values <0.05), but none remained significant after a stringent correction for the total number of tests performed.
The strongest signal emerged from SNPs in the promoter region (rs3808585) and in an intron (rs17426222, rs4732682, rs573514) of ADRA1A, all located within the same haplotype block. Some of the SNPs in HTR2A and COMT have already been reported by others, whereas other SNPs will need confirmation in independent samples.
Psychiatric genetics 04/2009; 19(3):134-41. · 2.33 Impact Factor
