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Pruim R.J.,Calvin College | Welch R.P.,University of Michigan | Sanna S.,CNR Institute of Neurogenetics and Neuropharmacology | Teslovich T.M.,University of Michigan | And 5 more authors.

Summary: Genome-wide association studies (GWAS) have revealed hundreds of loci associated with common human genetic diseases and traits. We have developed a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format. LocusZoom visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region. © The Author(s) 2010. Source

Galanello R.,University of Cagliari | Cao A.,CNR Institute of Neurogenetics and Neuropharmacology
Genetics in Medicine

Alpha-thalassemia is one of the most common hemoglobin genetic abnormalities and is caused by the reduced or absent production of the alpha globin chains. Alpha-thalassemia is prevalent in tropical and subtropical world regions where malaria was and still is epidemic, but as a consequence of the recent massive population migrations, alpha-thalassemia has become a relatively common clinical problem in North America, North Europe, and Australia. Alpha-thalassemia is very heterogeneous at a clinical and molecular level. Four clinical conditions of increased severity are recognized: the silent carrier state, the alpha-thalassemia trait, the intermediate form of hemoglobin H disease, and the hemoglobin Bart hydrops fetalis syndrome that is lethal in utero or soon after birth.Alpha-thalassemia is caused most frequently by deletions involving one or both alpha globin genes and less commonly by nondeletional defects. A large number of alpha-thalassemia alleles have been described and their interaction results in the wide spectrum of hematological and clinical phenotypes. Genotype-phenotype correlation has been only partly clarified. Carriers of alpha-thalassemia do not need any treatment. Usually, patients with hemoglobin H disease are clinically well and survive without any treatment, but occasional red blood cell transfusions may be needed if the hemoglobin level suddenly drops because of hemolytic or aplastic crisis likely due to viral infections. Hemoglobin Bart hydrops fetalis syndrome currently has no effective treatment although attempts at intrauterine transfusion and hematopoietic stem cell transplantation have been made. © 2011 Lippincott Williams & Wilkins. Source

Li Y.,University of North Carolina at Chapel Hill | Li Y.,University of Michigan | Sidore C.,CNR Institute of Neurogenetics and Neuropharmacology | Sidore C.,University of Sassari | And 4 more authors.
Genome Research

New sequencing technologies allow genomic variation to be surveyed in much greater detail than previously possible. While detailed analysis of a single individual typically requires deep sequencing, when many individuals are sequenced it is possible to combine shallow sequence data across individuals to generate accurate calls in shared stretches of chromosome. Here, we show that, as progressively larger numbers of individuals are sequenced, increasingly accurate genotype calls can be generated for a given sequence depth. We evaluate the implications of low-coverage sequencing for complex trait association studies. We systematically compare study designs based on genotyping of tagSNPs, sequencing of many individuals at depths ranging between 2x and 30x, and imputation of variants discovered by sequencing a subset of individuals into the remainder of the sample. We show that sequencing many individuals at low depth is an attractive strategy for studies of complex trait genetics. For example, for disease-associated variants with frequency >0.2%, sequencing 3000 individuals at 4x depth provides similar power to deep sequencing of >2000 individuals at 30x depth but requires only ∼20% of the sequencing effort. We also show low-coverage sequencing can be used to build a reference panel that can drive imputation into additional samples to increase power further. We provide guidance for investigators wishing to combine results from sequenced, genotyped, and imputed samples. © 2011 by Cold Spring Harbor Laboratory Press. Source

Sutin A.R.,U.S. National Institute on Aging | Terracciano A.,U.S. National Institute on Aging | Kitner-Triolo M.H.,U.S. National Institute on Aging | Uda M.,CNR Institute of Neurogenetics and Neuropharmacology | And 2 more authors.
Psychology and Aging

In a community-dwelling sample (N = 4,790; age range 14-94), we examined whether personality traits prospectively predicted performance on a verbal fluency task. Open, extraverted, and emotionally stable participants had better verbal fluency. At the facet level, dispositionally happy and self-disciplined participants retrieved more words; those prone to anxiety and depression and those who were deliberative retrieved fewer words. Education moderated the association between conscientiousness and fluency such that participants with lower education performed better on the fluency task if they were also conscientious. Age was not a moderator at the domain level, indicating that the personality-fluency associations were consistent across the life span. A disposition toward emotional vulnerability and being less open, less happy, and undisciplined may be detrimental to cognitive performance. © 2011 American Psychological Association. Source

Cao A.,CNR Institute of Neurogenetics and Neuropharmacology | Galanello R.,University of Cagliari
Genetics in Medicine

Beta-thalassemia is caused by the reduced (beta+) or absent (beta') synthesis of the beta globin chains of the hemoglobin tetramer. Three clinical and hematological conditions of increasing severity are recognized, i.e., the beta-thalassemia carrier state, thalassemia intermedia, and thalassemia major. The beta-thalassemia carrier state, which results from heterozygosity for beta-thalassemia, is clinically asymptomatic and is defined by specific hematological features. Thalassemia major is a severe transfusion-dependent anemia. Thalassemia intermedia comprehend a clinically and genotypically very heterogeneous group of thalassemia-like disorders, ranging in severity from the asymptomatic carrier state to the severe transfusion-dependent type. The clinical severity of beta-thalassemia is related to the extent of imbalance between the alpha and nonalpha globin chains. The beta globin (HBB) gene maps in the short arm of chromosome 11, in a region containing also the delta globin gene, the embryonic epsilon gene, the fetal A-gamma and G-gamma genes, and a pseudogene (ψB1). Beta-thalassemias are heterogeneous at the molecular level. More than 200 disease-causing mutations have been so far identified. The majority of mutations are single nucleotide substitutions, deletions, or insertions of oligonucleotides leading to frameshift. Rarely, beta-thalassemia results from gross gene deletion. In addition to the variation of the phenotype resulting from allelic heterogeneity at the beta globin locus, the phenotype of beta-thalassemia could also be modified by the action of genetic factors mapping outside the globin gene cluster and not influencing the fetal hemoglobin. Among these factors, the ones best delineated so far are those affecting bilirubin, iron, and bone metabolisms. Because of the high carrier rate for HBB mutations in certain populations and the availability of genetic counseling and prenatal diagnosis, population screening is ongoing in several at-risk populations in the Mediterranean. Population screening associated with genetic counseling was extremely useful by allowing couples at risk to make informed decision on their reproductive choices. Clinical management of thalassemia major consists in regular long-life red blood cell transfusions and iron chelation therapy to remove iron introduced in excess with transfusions. At present, the only definitive cure is bone marrow transplantation. Therapies under investigation are the induction of fetal hemoglobin with pharmacologic compounds and stem cell gene therapy. © 2010 Lippincott Williams & Wilkins. Source

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