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Find video protocols related to scientific articles indexed in Pubmed.
DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family.
Mov. Disord.
PUBLISHED: 08-20-2014
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Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.
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Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.
Nat Commun
PUBLISHED: 05-01-2014
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Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.
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Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.
Hum. Genet.
PUBLISHED: 04-14-2014
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To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.
PLoS ONE
PUBLISHED: 01-01-2014
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Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p?=?1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value?=?9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
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A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
J. Med. Genet.
PUBLISHED: 10-17-2013
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Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant.
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Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutations.
Orphanet J Rare Dis
PUBLISHED: 06-24-2013
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Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/results: We characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patients immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.
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Severe intellectual disability, West syndrome, Dandy-Walker malformation, and syndactyly in a patient with partial tetrasomy 17q25.3.
Am. J. Med. Genet. A
PUBLISHED: 06-14-2013
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We report on a de novo 0.5?Mb triplication (partial tetrasomy) of chromosome 17q25.3 in a 10-year-old girl with severe intellectual disability, infantile seizures (West syndrome), moderate hearing loss, Dandy-Walker malformation, microcephaly, craniofacial dysmorphism, striking cutaneous syndactyly (hands 3-4, feet 2-3), joint laxity, and short stature. The triplication resulted from the unusual combination of a terminal duplication at 17qter and a cryptic translocation of an extra copy of the same segment onto chromosome 10qter. The breakpoint at 17q25.3 was located within the FOXK2 gene. SNP chip analysis suggested that the rearrangement occurred during paternal meiosis involving both paternal chromosomes 17. © 2013 Wiley Periodicals, Inc.
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Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.
Ching-Yu Cheng, Maria Schache, M Kamran Ikram, Terri L Young, Jeremy A Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J M Verhoeven, Veluchamy A Barathi, Jiemin Liao, Pirro G Hysi, Joan E Bailey-Wilson, Beate St Pourcain, John P Kemp, George McMahon, Nicholas J Timpson, David M Evans, Grant W Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polašek, Alan F Wright, Najaf Amin, Elisabeth M van Leeuwen, James F Wilson, Craig E Pennell, Cornelia M van Duijn, Paulus T V M de Jong, Johannes R Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, , Kathryn P Burdon, Jamie E Craig, Sudha K Iyengar, Robert P Igo, Jonathan H Lass, Emily Y Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E Klein, S Mohsen Hosseini, Andrew D Paterson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K H Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W Hewitt, Cathy Williams, Ben A Oostra, Yik-Ying Teo, Christopher J Hammond, Dwight Stambolian, David A Mackey, Caroline C W Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N Baird.
Am. J. Hum. Genet.
PUBLISHED: 03-15-2013
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Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
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Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.
Hum. Mol. Genet.
PUBLISHED: 03-07-2013
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Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (Cooperative Health Research in the Region of Augsburg); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.
Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, , Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasatian, Sarayut Janmahasathian, Robert P Igo, Jonathan H Lass, Emily Chew, Sudha K Iyengar, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polašek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond.
Nat. Genet.
PUBLISHED: 01-16-2013
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Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
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Anal atresia, coloboma, microphthalmia, and nasal skin tag in a female patient with 3.5?Mb deletion of 3q26 encompassing SOX2.
Am. J. Med. Genet. A
PUBLISHED: 01-11-2013
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A full term female newborn presented with prominent forehead, bilateral microphthalmia, iris coloboma and cataract, wide intercanthal distance, large, low-set and protruding ears, skin tag at the left nasal nostril, imperforate anus with rectovestibular fistula, and postnatal growth delay with brachymicrocephaly. A marker chromosome was not detectable and the copy number of 22q11 was normal. However, array CGH revealed a 3.5?Mb microdeletion of chromosome region 3q26.32-3q26.33 (chr. 3: 178,598,162-182,114,483; hg19) which comprised the SOX2 gene. While SOX2 haploinsufficiency is known to cause microphthalmia and coloboma, it has not been described before in patients with anal atresia.
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Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders.
PLoS ONE
PUBLISHED: 01-01-2013
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Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinsons disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n?=?563), FTLD (n?=?133) and PSP (n?=?94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.
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Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.
Am. J. Hum. Genet.
PUBLISHED: 08-01-2011
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The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.
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Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.
BMC Neurol
PUBLISHED: 06-19-2011
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Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features.
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Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.
Diabetes Care
PUBLISHED: 05-20-2011
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To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation.
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MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease.
J. Med. Genet.
PUBLISHED: 05-14-2011
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Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case-control association study of these variants in ESRD patients was performed.
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Sampling GWAS subjects from risk populations.
Genet. Epidemiol.
PUBLISHED: 02-16-2011
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Power, i.e. sample size, is a crucial issue in genome-wide association studies (GWAS) on disorders generated by a multitude of weak genetic effects. Here, we examine the influence of sampling cases and/or controls from populations that are subjected to an external risk factor (such as smoking or nutritional factors). We use an additive threshold model and derive the necessary sample size as function of the external risk factors strength and of the sampling scheme. If both cases and controls are sampled from the risk population, a loss of power must be expected. The loss of power (i.e. the increase of the necessary sample size) is even larger if only the cases are sampled from the risk population, whereas the inverse scheme (nonrisk cases and risk controls) provides a gain of power since nonrisk cases are enriched for disease-favouring alleles while risk controls are enriched for protective alleles. For small effect sizes, we derive simple approximations in analytically closed form. A strategy of GWAS sample collection from risk populations minimizing the necessary sample sizes may thus be deduced that generally applies as long as strong gene-environment interactions can be excluded.
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3.7 Mb tandem microduplication in chromosome 5p13.1-p13.2 associated with developmental delay, macrocephaly, obesity, and lymphedema. Further characterization of the dup(5p13) syndrome.
Eur J Med Genet
PUBLISHED: 01-04-2011
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In a male patient with developmental delay, autistic behaviour, obesity, lymphedema, hypertension, macrocephaly, and facial features of chromosome 5p duplication (trisomy 5p) a 3.7 Mb de novo tandem microduplication of 5p13.1-13.2 (rs4703415-rs261752, i.e., chr5:35.62-39.36 Mb) was identified. This observation contributes to the characterization and dissection of the 5p13 duplication syndrome. The possible role of increased NIPBL gene dosage is discussed.
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Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels.
Hum. Mol. Genet.
PUBLISHED: 12-10-2010
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The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 × 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct.
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Common variants at 10 genomic loci influence hemoglobin A?(C) levels via glycemic and nonglycemic pathways.
Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia-Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S Sandhu, Matthew M Heeney, Joseph M Devaney, Muredach P Reilly, Sally L Ricketts, Alexandre F R Stewart, Benjamin F Voight, Christina Willenborg, Benjamin Wright, David Altshuler, Dan Arking, Beverley Balkau, Daniel Barnes, Eric Boerwinkle, Bernhard Böhm, Amélie Bonnefond, Lori L Bonnycastle, Dorret I Boomsma, Stefan R Bornstein, Yvonne Böttcher, Suzannah Bumpstead, Mary Susan Burnett-Miller, Harry Campbell, Antonio Cao, John Chambers, Robert Clark, Francis S Collins, Josef Coresh, Eco J C de Geus, Mariano Dei, Panos Deloukas, Angela Döring, Josephine M Egan, Roberto Elosua, Luigi Ferrucci, Nita Forouhi, Caroline S Fox, Christopher Franklin, Maria Grazia Franzosi, Sophie Gallina, Anuj Goel, Jurgen Graessler, Harald Grallert, Andreas Greinacher, David Hadley, Alistair Hall, Anders Hamsten, Caroline Hayward, Simon Heath, Christian Herder, Georg Homuth, Jouke-Jan Hottenga, Rachel Hunter-Merrill, Thomas Illig, Anne U Jackson, Antti Jula, Marcus Kleber, Christopher W Knouff, Augustine Kong, Jaspal Kooner, Anna Köttgen, Peter Kovacs, Knut Krohn, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Mark Lathrop, Cécile Lecoeur, Man Li, Mingyao Li, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Anders Malarstig, Massimo Mangino, María Teresa Martínez-Larrad, Winfried März, Wendy L McArdle, Ruth McPherson, Christa Meisinger, Thomas Meitinger, Olle Melander, Karen L Mohlke, Vincent E Mooser, Mario A Morken, Narisu Narisu, David M Nathan, Matthias Nauck, Chris O'Donnell, Konrad Oexle, Nazario Olla, James S Pankow, Felicity Payne, John F Peden, Nancy L Pedersen, Leena Peltonen, Markus Perola, Ozren Polašek, Eleonora Porcu, Daniel J Rader, Wolfgang Rathmann, Samuli Ripatti, Ghislain Rocheleau, Michael Roden, Igor Rudan, Veikko Salomaa, Richa Saxena, David Schlessinger, Heribert Schunkert, Peter Schwarz, Udo Seedorf, Elizabeth Selvin, Manuel Serrano-Ríos, Peter Shrader, Angela Silveira, David Siscovick, Kjioung Song, Timothy D Spector, Kari Stefansson, Valgerdur Steinthorsdottir, David P Strachan, Rona Strawbridge, Michael Stumvoll, Ida Surakka, Amy J Swift, Toshiko Tanaka, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Anke Tönjes, Gianluca Usala, Veronique Vitart, Henry Völzke, Henri Wallaschofski, Dawn M Waterworth, Hugh Watkins, H-Erich Wichmann, Sarah H Wild, Gonneke Willemsen, Gordon H Williams, James F Wilson, Juliane Winkelmann, Alan F Wright, , Carina Zabena, Jing Hua Zhao, Stephen E Epstein, Jeanette Erdmann, Hakon H Hakonarson, Sekar Kathiresan, Kay-Tee Khaw, Robert Roberts, Nilesh J Samani, Mark D Fleming, Robert Sladek, Goncalo Abecasis, Michael Boehnke, Philippe Froguel, Leif Groop, Mark I McCarthy, W H Linda Kao, Jose C Florez, Manuela Uda, Nicholas J Wareham, Inês Barroso, James B Meigs.
Diabetes
PUBLISHED: 09-21-2010
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Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.
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A remark on rare variants.
J. Hum. Genet.
PUBLISHED: 03-05-2010
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The genetic architecture of a disease determines the epidemiological methods for its examination. Recently, Bodmer and Bonilla suggested that moderately strong, moderately rare variants contribute substantially to the genetic population attributable risk (PAR) of common diseases. In the first part of this communication, I provide a concise reconstruction of their deliberation. Variants contributing to human disease can be identified by linkage or by association tests. Risch and Merikangas analyzed the power of these tests by comparing the affected sib-pair linkage test (ASP) and the transmission disequilibrium association test (TDT). In the second part of this paper, I give an accessible reconstruction of this comparison and derive simple approximations in the low allele frequency range, directly showing that the linkage test is much more sensitive to a decrease of frequency or effect size. In the third part, I analyze a disease model whose genetic architecture is proportional to Kimuras infinite sites model. The relation between a variants selection coefficient and its effect size in disease generation is assumed to be simple, and the number of contributing genetic variants is determined by the sum of their approximative PAR contributions. An association test (TDT) is finally applied to this disease model. For different ranges of effect size and allele frequency, I derive the minimal sample size necessary to detect at least one contributing variant. It turns out that, although the majority of contributing variants is not accessible with realistic sample sizes, a minimum of sample size may be given for moderately strong variants in the 1% frequency range.
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Recurrent hypoglycemia due to growth hormone deficiency in an infant with Turner syndrome.
J. Pediatr. Endocrinol. Metab.
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Growth hormone (GH) deficiency may occur in Turner syndrome (TS), but infantile hypoglycemia attributable to TS with GH deficiency has not been reported before.
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Dilution of candidates: the case of iron-related genes in restless legs syndrome.
Eur. J. Hum. Genet.
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Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.
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Cryptic del/dup aberration of 60.6 Mb at 5q15-5q23.3 predicting adult-onset leukodystrophy.
Eur J Med Genet
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We report on a de novo interstitial del/dup aberration consisting of a 13.3 Mb deletion of 5q15-5q21.3 (92.1-105.4 Mb, hg19) and a 23.6 Mb tandem direct duplication of 5q21.3-5q23.3 (106.1-129.7 Mb, hg19). Although the aberration covered a total of 60.6 Mb, it was cryptic, i.e., not detectable by karyotyping at a resolution of 430 bands. Array-CGH indicated a diploid region of 0.6 Mb between the duplicated and the deleted segment. The aberration affected a 14-month-old boy conceived after intracytoplasmic sperm injection who presented with developmental delay, muscular hypotonia, partial agenesis of the corpus callosum, prominent forehead, low set ears, hypertelorism, hyperopia, wide-bridged nose, retrognathia, high palate, and cryptorchidism. The duplicated segment comprised the LMNB1 gene, thus predicting adult-onset autosomal-dominant leukodystrophy and revealing a temporal dimension of the phenotype. Counseling problems implicated by this prediction include "the right not to know" that the patient might want to exercise when coming of age.
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PSEA: Phenotype Set Enrichment Analysis--a new method for analysis of multiple phenotypes.
Genet. Epidemiol.
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Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request.
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Familial pineocytoma.
Acta Neurochir (Wien)
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We present the first report on familial pineocytoma. The propositus, a 31-year-old man, presented with incontinence due to a cystic and haemorrhagic tumour of the pineal region. His 34-year-old sister, who had suffered from tinnitus for several years, also had a pineal tumour. Histopathology following tumour resection revealed pineocytomas (WHO grade 1). Cerebral MRI examinations of the patients brother and father did not reveal any pineal region abnormalities. Their mother had developed breast cancer at the age of 43. Although not impossible, it is rather unlikely that pineocytomas occurring in siblings are pure coincidence because of the rarity of this type of tumour.
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Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.
Virginie J M Verhoeven, Pirro G Hysi, Seang-Mei Saw, Veronique Vitart, Alireza Mirshahi, Jeremy A Guggenheim, Mary Frances Cotch, Kenji Yamashiro, Paul N Baird, David A Mackey, Robert Wojciechowski, M Kamran Ikram, Alex W Hewitt, Priya Duggal, Sarayut Janmahasatian, Chiea-Chuen Khor, Qiao Fan, Xin Zhou, Terri L Young, E-Shyong Tai, Liang-Kee Goh, Yi-Ju Li, Tin Aung, Eranga Vithana, Yik-Ying Teo, Wanting Tay, Xueling Sim, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polašek, Harry Campbell, James F Wilson, Brian W Fleck, Isao Nakata, Nagahisa Yoshimura, Ryo Yamada, Fumihiko Matsuda, Kyoko Ohno-Matsui, Abhishek Nag, George McMahon, Beate St Pourcain, Yi Lu, Jugnoo S Rahi, Phillippa M Cumberland, Shomi Bhattacharya, Claire L Simpson, Larry D Atwood, Xiaohui Li, Leslie J Raffel, Federico Murgia, Laura Portas, Dominiek D G Despriet, Leonieke M E van Koolwijk, Christian Wolfram, Karl J Lackner, Anke Tönjes, Reedik Mägi, Terho Lehtimäki, Mika Kähönen, Tonu Esko, Andres Metspalu, Taina Rantanen, Olavi Pärssinen, Barbara E Klein, Thomas Meitinger, Timothy D Spector, Ben A Oostra, Albert V Smith, Paulus T V M de Jong, Albert Hofman, Najaf Amin, Lennart C Karssen, Fernando Rivadeneira, Johannes R Vingerling, Guðný Eiríksdóttir, Vilmundur Gudnason, Angela Döring, Thomas Bettecken, André G Uitterlinden, Cathy Williams, Tanja Zeller, Raphaele Castagné, Konrad Oexle, Cornelia M van Duijn, Sudha K Iyengar, Paul Mitchell, Jie Jin Wang, René Höhn, Norbert Pfeiffer, Joan E Bailey-Wilson, Dwight Stambolian, Tien-Yin Wong, Christopher J Hammond, Caroline C W Klaver.
Hum. Genet.
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Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
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