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Admixture mapping and subsequent fine-mapping suggests a biologically relevant and novel association on chromosome 11 for type 2 diabetes in African Americans.
Jeff JM, Armstrong LL, Ritchie MD, Denny JC, Kho AN, Basford MA, Wolf WA, Pacheco JA, Li R, Chisholm RL, Roden DM, Hayes MG, Crawford DC
(2014) PLoS One 9: e86931
MeSH Terms: African Continental Ancestry Group, Chromosome Mapping, Chromosomes, Human, Pair 11, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide
Show Abstract · Added May 23, 2014
Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10(-8) by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.
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8 MeSH Terms
Cytogenetic prognostication within medulloblastoma subgroups.
Shih DJ, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M, Luu B, Yao Y, Wang X, Dubuc AM, Garzia L, Peacock J, Mack SC, Wu X, Rolider A, Morrissy AS, Cavalli FM, Jones DT, Zitterbart K, Faria CC, Schüller U, Kren L, Kumabe T, Tominaga T, Shin Ra Y, Garami M, Hauser P, Chan JA, Robinson S, Bognár L, Klekner A, Saad AG, Liau LM, Albrecht S, Fontebasso A, Cinalli G, De Antonellis P, Zollo M, Cooper MK, Thompson RC, Bailey S, Lindsey JC, Di Rocco C, Massimi L, Michiels EM, Scherer SW, Phillips JJ, Gupta N, Fan X, Muraszko KM, Vibhakar R, Eberhart CG, Fouladi M, Lach B, Jung S, Wechsler-Reya RJ, Fèvre-Montange M, Jouvet A, Jabado N, Pollack IF, Weiss WA, Lee JY, Cho BK, Kim SK, Wang KC, Leonard JR, Rubin JB, de Torres C, Lavarino C, Mora J, Cho YJ, Tabori U, Olson JM, Gajjar A, Packer RJ, Rutkowski S, Pomeroy SL, French PJ, Kloosterhof NK, Kros JM, Van Meir EG, Clifford SC, Bourdeaut F, Delattre O, Doz FF, Hawkins CE, Malkin D, Grajkowska WA, Perek-Polnik M, Bouffet E, Rutka JT, Pfister SM, Taylor MD
(2014) J Clin Oncol 32: 886-96
MeSH Terms: Adolescent, Biomarkers, Tumor, Child, Child, Preschool, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Cytogenetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Humans, In Situ Hybridization, Fluorescence, Infant, Kruppel-Like Transcription Factors, Male, Medulloblastoma, Nuclear Proteins, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-myc, Reproducibility of Results, Risk Assessment, Risk Factors, Tissue Array Analysis, Wnt Proteins, Young Adult, Zinc Finger Protein Gli2
Show Abstract · Added March 21, 2014
PURPOSE - Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
PATIENTS AND METHODS - Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.
RESULTS - Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
CONCLUSION - Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
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29 MeSH Terms
Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, Khan S, Maranian MJ, O'Reilly M, Hillman KM, Betts JA, Carroll T, Bailey PJ, Dicks E, Beesley J, Tyrer J, Maia AT, Beck A, Knoblauch NW, Chen C, Kraft P, Barnes D, González-Neira A, Alonso MR, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Conroy D, Dennis J, Bolla MK, Wang Q, Hopper JL, Southey MC, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Loehberg CR, Ekici AB, Beckmann MW, Peto J, dos Santos Silva I, Johnson N, Aitken Z, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias Perez JI, Benitez J, Anton-Culver H, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Engel C, Brauch H, Hamann U, Justenhoven C, GENICA Network, Aaltonen K, Heikkilä P, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Sueta A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, kConFab Investigators, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Peeters S, Smeets A, Floris G, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Sardella D, Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Ng CH, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Schoof N, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Balasubramanian SP, Blot W, Signorello LB, Cai Q, Pharoah PD, Healey CS, Shah M, Pooley KA, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Sng JH, Sim X, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, McKay J, Toland AE, Ambrosone CB, Yannoukakos D, Godwin AK, Shen CY, Hsiung CN, Wu PE, Chen ST, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, Dunning AM
(2013) Am J Hum Genet 92: 489-503
MeSH Terms: Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 11, Cyclin D1, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4
Show Abstract · Added March 10, 2014
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Circulating CD34(+) progenitor cell frequency is associated with clinical and genetic factors.
Cohen KS, Cheng S, Larson MG, Cupples LA, McCabe EL, Wang YA, Ngwa JS, Martin RP, Klein RJ, Hashmi B, Ge Y, O'Donnell CJ, Vasan RS, Shaw SY, Wang TJ
(2013) Blood 121: e50-6
MeSH Terms: Aged, Antigens, CD34, Biomarkers, Tumor, Cardiovascular Diseases, Carrier Proteins, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 11, DNA-Binding Proteins, Female, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Massachusetts, Middle Aged, Oligonucleotide Array Sequence Analysis, Phosphopyruvate Hydratase, Prevalence, Risk Factors, Sex Distribution, Smoking, Tumor Suppressor Proteins
Show Abstract · Added April 15, 2014
Circulating blood CD34(+) cells consist of hematopoietic stem/progenitor cells, angiogenic cells, and endothelial cells. In addition to their clinical use in hematopoietic stem cell transplantation, CD34(+) cells may also promote therapeutic neovascularization. Therefore, understanding the factors that influence circulating CD34(+) cell frequency has wide implications for vascular biology in addition to stem cell transplantation. In the present study, we examined the clinical and genetic characteristics associated with circulating CD34(+) cell frequency in a large, community-based sample of 1786 Framingham Heart Study participants.Among subjects without cardiovascular disease (n = 1595), CD34(+) frequency was inversely related to older age, female sex, and smoking. CD34(+) frequency was positively related to weight, serum total cholesterol, and statin therapy. Clinical covariates accounted for 6.3% of CD34(+) variability. CD34(+) frequency was highly heritable (h(2) = 54%; P < .0001). Genome-wide association analysis of CD34(+) frequency identified suggestive associations at several loci, including OR4C12 (chromosome 11; P = 6.7 × 10(-7)) and ENO1 and RERE (chromosome 1; P = 8.8 × 10(-7)). CD34(+) cell frequency is reduced in older subjects and is influenced by environmental factors including smoking and statin use. CD34(+) frequency is highly heritable. The results of the present study have implications for therapies that use CD34(+) cell populations and support efforts to better understand the genetic mechanisms that underlie CD34(+) frequency.
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24 MeSH Terms
Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.
Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, Shen H, Park SK, Chen K, Shen CY, Ren Z, Haiman CA, Matsuo K, Kim MK, Khoo US, Iwasaki M, Zheng Y, Xiang YB, Gu K, Rothman N, Wang W, Hu Z, Liu Y, Yoo KY, Noh DY, Han BG, Lee MH, Zheng H, Zhang L, Wu PE, Shieh YL, Chan SY, Wang S, Xie X, Kim SW, Henderson BE, Le Marchand L, Ito H, Kasuga Y, Ahn SH, Kang HS, Chan KY, Iwata H, Tsugane S, Li C, Shu XO, Kang DH, Zheng W
(2012) PLoS Genet 8: e1002532
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, Asian Continental Ancestry Group, Breast Neoplasms, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 6, Estrogen Receptor alpha, Far East, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged
Show Abstract · Added December 10, 2013
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.
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14 MeSH Terms
Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Järvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppönen E, Spector TD
(2010) Lancet 376: 180-8
MeSH Terms: Canada, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Cohort Studies, Dietary Supplements, Europe, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Immunoassay, International Cooperation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Seasons, United States, Vitamin D, Vitamin D Deficiency
Show Abstract · Added April 15, 2014
BACKGROUND - Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
METHODS - We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.
FINDINGS - Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.
INTERPRETATION - Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.
FUNDING - Full funding sources listed at end of paper (see Acknowledgments).
Copyright 2010 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Examination of tetrahydrobiopterin pathway genes in autism.
Schnetz-Boutaud NC, Anderson BM, Brown KD, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA, Haines JL
(2009) Genes Brain Behav 8: 753-7
MeSH Terms: Adolescent, Autistic Disorder, Biopterin, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 11, DNA Mutational Analysis, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genotype, Humans, Male, Phosphorus-Oxygen Lyases, Polymorphism, Single Nucleotide, Signal Transduction, Young Adult
Show Abstract · Added March 5, 2014
Autism is a complex disorder with a high degree of heritability and significant phenotypic and genotypic heterogeneity. Although candidate gene studies and genome-wide screens have failed to identify major causal loci associated with autism, numerous studies have proposed association with several variations in genes in the dopaminergic and serotonergic pathways. Because tetrahydrobiopterin (BH4) is the essential cofactor in the synthesis of these two neurotransmitters, we genotyped 25 SNPs in nine genes of the BH4 pathway in a total of 403 families. Significant nominal association was detected in the gene for 6-pyruvoyl-tetrahydropterin synthase, PTS (chromosome 11), with P = 0.009; this result was not restricted to an affected male-only subset. Multilocus interaction was detected in the BH4 pathway alone, but not across the serotonin, dopamine and BH4 pathways.
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20 MeSH Terms
Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon.
Clark ES, Brown B, Whigham AS, Kochaishvili A, Yarbrough WG, Weaver AM
(2009) Oncogene 28: 431-44
MeSH Terms: Animals, Apoptosis, Autocrine Communication, Carcinoma, Squamous Cell, Cell Proliferation, Chromosomes, Human, Pair 11, Coculture Techniques, Cortactin, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Humans, Mice, Mice, Nude, Neoplasm Invasiveness, Nerve Growth Factors, RNA, Small Interfering, Rats, Trachea, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
11q13 amplification is a late-stage event in several cancers that is often associated with poor prognosis. Among 11q13-amplified genes, the actin assembly protein cortactin/CTTN is considered a likely candidate for direct involvement in tumor progression because of its cell motility-enhancing functions. We modulated cortactin expression in head and neck squamous cell carcinoma (HNSCC) cell lines. Cortactin expression levels directly correlated with tumor size, vascularization and cell proliferation in an orthotopic HNSCC in vivo model. In contrast, under normal in vitro culture conditions, cortactin expression levels had no effect on cell proliferation. However, cell lines in which cortactin expression was reduced by knockdown (KD) grew poorly in vitro under harsh conditions of growth factor deprivation, anchorage independence and space constraint. In contrast, overexpression of cortactin enhanced in vitro growth under the same harsh conditions. Surprisingly, defects in growth factor-independent proliferation of cortactin-KD cells were rescued by coculture with cortactin-expressing cells. As the cocultured cells are separated by permeable filters, cortactin-expressing cells must secrete growth-supporting autocrine factors to rescue the cortactin-KD cells. Overall, cortactin expression modulates multiple cellular traits that may allow survival in a tumor environment, suggesting that the frequent overexpression of cortactin in tumors is not an epiphenomenon but rather promotes tumor aggressiveness.
1 Communities
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19 MeSH Terms
Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).
Coldren CD, Lai Z, Shragg P, Rossi E, Glidewell SC, Zuffardi O, Mattina T, Ivy DD, Curfs LM, Mattson SN, Riley EP, Treier M, Grossfeld PD
(2009) Neurogenetics 10: 89-95
MeSH Terms: Adolescent, Adult, Animals, Child, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 11, Cognition Disorders, Female, Homeodomain Proteins, Humans, Jacobsen Distal 11q Deletion Syndrome, Male, Mental Disorders, Mice, Microarray Analysis, Nerve Tissue Proteins, Neurogranin, Prospective Studies, Young Adult
Show Abstract · Added November 17, 2011
We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions,
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20 MeSH Terms
Genome-wide linkage analyses of quantitative and categorical autism subphenotypes.
Liu XQ, Paterson AD, Szatmari P, Autism Genome Project Consortium
(2008) Biol Psychiatry 64: 561-70
MeSH Terms: Autistic Disorder, Child, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 15, Female, Genetic Linkage, Genetic Markers, Genome-Wide Association Study, Humans, Interpersonal Relations, Male, Phenotype, Verbal Behavior
Show Abstract · Added February 20, 2014
BACKGROUND - The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.
METHODS - In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ > or = 70.
RESULTS - When the ASD families with IQ > or = 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits.
CONCLUSIONS - This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.
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13 MeSH Terms