Increased levels of fetal hemoglobin (HbF, α2γ2) are of no consequence in healthy adults, but confer major clinical benefits in patients with sickle cell anemia (SCA) and β thalassemia, diseases that ...represent major public health problems. Inter-individual HbF variation is largely genetically controlled, with one extreme caused by mutations involving the β globin gene (HBB) complex, historically referred to as pancellular hereditary persistence of fetal hemoglobin (HPFH). These Mendelian forms of HPFH are rare and do not explain the common form of heterocellular HPFH which represents the upper tail of normal HbF variation, and is clearly inherited as a quantitative genetic trait. Genetic studies have identified three major quantitative trait loci (QTLs) (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23, and BCL11A on chromosome 2p16) that account for 20–50% of the common variation in HbF levels in patients with SCA and β thalassemia, and in healthy adults. Two of the major QTLs include oncogenes, emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. The review traces the story of HbF quantitative genetics that uncannily mirrors the changing focus in genetic methodology, from candidate genes through positional cloning, to genome-wide association, that have expedited the dissection of the genetic architecture underlying HbF variability. These genetic results have already provided remarkable insights into molecular mechanisms that underlie the hemoglobin ‘switch’.
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 ...transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
Aims/hypothesis
Mutations in
BSCL
2/seipin cause Berardinelli–Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin ...resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype.
Methods
Bscl2
−/−
mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation.
Results
As observed in humans,
Bscl2
−/−
mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However,
Bscl2
−/−
mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in
Bscl2
−/−
MEFs. In vivo treatment of
Bscl2
−/−
mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice.
Conclusions/interpretation
Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in
Bscl2
−/−
mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.
A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre ...genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional reactivity, and determining their predictive value for the development of frequent psychiatric disorders. Comprehensive behavioural and neuropsychological characterization, functional and structural neuroimaging and genome-wide association analyses of 2000 14-year-old adolescents are combined with functional genetics in animal and human models. Results will be validated in 1000 adolescents from the Canadian Saguenay Youth Study. The sample will be followed up longitudinally at the age of 16 years to investigate the predictive value of genetics and intermediate phenotypes for the development of frequent psychiatric disorders. This review describes the strategies the IMAGEN consortium used to meet the challenges posed by large-scale multicentre imaging-genomics investigations. We provide detailed methods and Standard Operating Procedures that we hope will be helpful for the design of future studies. These include standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large-scale genetic neuroimaging analyses.
Introduction La lipodystrophie congénitale généralisée de Berardinelli-Seip (BSCL) est caractérisée par une absence de tissu adipeux et une insulino-résistance sévère. Elle est souvent liée à ...l’altération bi-allélique de BSCL2 codant la seipine de fonction encore inconnue. Matériels et méthodes Nous avons caractérisé le phénotype métabolique des souris-Bscl2−/− et développé un modèle de fibroblastes embryonnaires (MEFs) capables de se différencier in vitro en adipocytes. Résultats La microtomographie à rayon-X montre que les souris-Bscl2−/− sont lipodystrophiques dès l’âge de 6 semaines, avec une baisse de 80 % des taux de leptine et d’adiponectine. Les données in vitro indiquent que l’absence de tissu adipeux serait due à la combinaison d’un défaut d’adipogenèse et de lipolyse. Seulement 10 % des MEFs-Bscl2−/− se différencient en adipocytes (vs 80 % pour les MEFs-sauvages) avec une réduction de l’induction de l’expression de PPAR ? et de son gène cible AP2. Ces défauts de différenciation sont réversés par la rosiglitazone. Dans les adipocytes-Bscl2−/−, l’hydrolyse des triglycérides est augmentée de 3 fois (p < 0,05). Les tests métaboliques démontrent que les souris-Bscl2−/− sont intolérantes au glucose et insulino-résistantes. Alors que ces souris sont hyperglycémiques à l’état nourri (1.88 ± 0,44 vs 1.22 ± 0,13 g/L, p < 0,05), leur glycémie s’abaisse après 12 h de jeûne (0,95 ± 0,07 vs 1.27 ± 0,08 g/L, p < 0,001). Le jeûne s’accompagne également d’une perte de poids sévère (2.50 ± 0,62 vs 0,86 ± 0,58 g) et d’une hypothermie (35.3 ± 0,6 vs 37.2 ± 0,2°C; p < 0,0005). De façon surprenante, les souris-Bscl2−/− sont hypotriglycéridémiques à l’état nourri, avec une chute supplémentaire de 80 % des triglycérides après 12 h de jeûne (vs 45 % chez les souris sauvages, p < 0,0001). Cette hypotriglycéridémie n’est pas liée à une baisse de la production hépatique des VLDL ni à une augmentation de l’activité lipase. Conclusion Nos données montrent que la seipine joue un rôle clé dans l’adipogenèse et la capacité de stockage des adipocytes mais aussi dans l’adaptabilité au jeûne.
Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for ...tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.
We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a ...French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.
Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory ...infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset <or=4 yrs) were higher in carriers of risk genotypes (OR 3.42-6.36) than in noncarriers (OR 1.84-2.44; p-value for interaction 0.02-0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84-7.16 in carriers and 1.74-2.25 in noncarriers; p-value for interaction 0.008-0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.
Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional ...genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10(-7)) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.
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