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result(s) for
"Lathrop, M"
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Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology
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.
Journal Article
Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice
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.
Journal Article
SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study
A genomewide screen of patients with myopathy who were taking high-dose simvastatin (80 mg per day) showed a strong association between myopathy and variants of
SLCO1B1,
which encodes an organic anion–transporting polypeptide. Approximately 60% of the cases of myopathy could be attributed to these variants. The association was replicated in an independent study. Genotyping
SLCO1B1
variants may be helpful for tailoring the dosage of statins and safety monitoring.
A genomewide screen of patients with myopathy who were taking high-dose simvastatin showed a strong association between myopathy and variants of
SLCO1B1,
which encodes an organic anion–transporting polypeptide.
Evidence from large-scale, randomized studies shows that statin therapy reduces the incidence of heart attacks, strokes, and revascularization procedures by about one fifth for each reduction of 40 mg per deciliter (1 mmol per liter) in the low-density lipoprotein (LDL) cholesterol level.
1
In rare cases, statins can cause muscle pain or weakness in association with elevated creatine kinase levels (i.e., myopathy), and occasionally, this leads to muscle breakdown and myoglobin release (i.e., rhabdomyolysis), with a risk of renal failure and death.
2
The mechanisms by which statins cause myopathy remain unknown but appear to be related to statin concentrations in the . . .
Journal Article
The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology
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.
Journal Article
Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project
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.
Journal Article
Nicotine consumption is regulated by a human polymorphism in dopamine neurons
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.
Journal Article
Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222
Background:
Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in
TP53
causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in
TP53
may also contribute to the risk of developing glioma.
Methods:
To comprehensively evaluate the impact of variation in
TP53
on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.
Results:
The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (
P
=6.86 × 10
−24
, minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.
Conclusion:
Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired
TP53
inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of
TP53
leading to impaired 3′-end processing of
TP53
mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.
Journal Article
Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma
The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level
P
-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module. We identified a module of 91 genes with a significant joint effect on childhood-onset asthma (
P
< 10
−5
). This module contained a core subnetwork including genes at known asthma loci and five peripheral subnetworks including relevant candidates. Notably, the core genes were connected to
APP
(encoding amyloid beta precursor protein), a major player in Alzheimer’s disease that is known to have immune and inflammatory components. Functional analysis of the module genes revealed four gene clusters involved in innate and adaptive immunity, chemotaxis, cell-adhesion and transcription regulation, which are biologically meaningful processes that may underlie asthma risk. Our findings provide important clues for future research into asthma aetiology.
Journal Article
Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the
ZNF292
gene (rs1925690;
P
-value=2.6 × 10
−8
; corrected
P
-value for equivalent number of independent quantitative traits=7.7 × 10
−8
) and an intergenic SNP, flanking the
ARPP-21
gene, with an overall effect on entorhinal cortical thickness (rs11129640;
P
-value=5.6 × 10
−8
; corrected
P
-value=1.7 × 10
−7
). Gene-wide scoring also highlighted
PICALM
as the most significant gene associated with entorhinal cortical thickness (
P
-value=6.7 × 10
−6
).
Journal Article