81 research outputs found
Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene
To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (FundaciĂł ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 Ă 10 - 9)
The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (Pâ€2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (Pâ€3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (Pâ€4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions
Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study
Comprehensivemetabolite profiling capturesmany highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serumamino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6million genotyped and imputed variants in 8545 nondiabetic Finnishmen fromtheMETabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966).We identified five novel loci associated with amino acid levels (P = < 5Ă10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3Ă10-26); ZFHX3 (chr16:73326579,minor allele frequency (MAF) = 0.42%, P = 3.6Ă10-9), LIPC (rs10468017, P = 1.5Ă10-8), and WWOX (rs9937914, P = 3.8Ă10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8Ă10-9). Gene-based tests identified two novel genes harboringmissense variants ofMAF < 1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5Ă10-6) and BCAT2 with valine (Pgene = 7.4Ă10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017,MAF=0.95%, Pconditional = 5.8Ă10-40) with glycine levels and HAL (rs141635447,MAF = 0.46%, Pconditional = 9.4Ă10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend < 0.001). These novel signals provide further insight into the molecularmechanisms of amino acidmetabolismand potentially, their perturbations in disease
New insights into the genetic etiology of Alzheimer's disease and related dementias.
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Observation of and search for decays
The first observation of the decay is reported
using proton-proton collision data corresponding to an integrated luminosity of
recorded by the LHCb experiment at centre-of-mass energies
of 7 and 8 TeV. The resonance is produced in the decay . The product of branching fractions normalised to that for
the intermediate state, , is measured to be
\begin{align*} {\cal R}_{\eta_{c}(2S)}\equiv\frac{{\mathcal B}(B^{+} \to
\eta_{c}(2S) K^{+}) \times {\mathcal B}(\eta_{c}(2S) \to p \bar p)}{{\mathcal
B}(B^{+} \to J/\psi K^{+}) \times {\mathcal B}(J/\psi\to p \bar p)} =~& (1.58
\pm 0.33 \pm 0.09)\times 10^{-2}, \end{align*} where the first uncertainty is
statistical and the second systematic. No signals for the decays and
are seen, and the 95\% confidence level upper limits on their relative
branching ratios are % found to be and
. In addition, the mass differences between the
and the states, between the and the
states, and the natural width of the are measured as
\begin{align*} M_{J/\psi} - M_{\eta_{c}(1S)} =~& 110.2 \pm 0.5 \pm 0.9 \rm \,
MeV, M_{\psi(2S)} -M_{\eta_{c}(2S)} =~ & 52.5 \pm 1.7 \pm 0.6 \rm \, MeV,
\Gamma_{\eta_{c}(1S)} =~& 34.0 \pm 1.9 \pm 1.3 \rm \, MeV. \end{align*}Comment: 16 pages, 2 figures All figures and tables, along with any
supplementary material and additional information, are available at
https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-016.htm
Measurement of asymmetries in and decays
See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-041.html - Submitted to Phys. Lett. BInternational audienceA search for CP violation in D±âηâČϱ and D±sâηâČϱ decays is performed using proton-proton collision data, corresponding to an integrated luminosity of 3 fbâ1, recorded by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The measured CP-violating charge asymmetries are ACP(D±âηâČϱ)=(â0.61±0.72±0.55±0.12)% and ACP(D±sâηâČϱ)=(â0.82±0.36±0.24±0.27)%, where the first uncertainties are statistical, the second systematic, and the third are the uncertainties on the ACP(D±âK0Sϱ) and ACP(D±sâÏϱ) measurements used for calibration. The results represent the most precise measurements of these asymmetries to date
Measurement of , , and production asymmetries in 7 and 8 TeV proton-proton collisions
See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-062.html - Submitted to Phys. Lett. B.International audienceThe B0, B0s, B+ and Î0b hadron production asymmetries are measured using a data sample corresponding to an integrated luminosity of 3.0 fbâ1, collected by the LHCb experiment in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. The measurements are performed as a function of transverse momentum and rapidity of the b hadrons within the LHCb detector acceptance. The overall production asymmetries, integrated over transverse momentum and rapidity, are also determined
Search for violation in the phase space of decays
A search for time-integrated violation in the Cabibbo-suppressed decay
\mbox{D^0\rightarrow\pi^+\pi^-\pi^+\pi^-} is performed using an unbinned,
model-independent technique known as the energy test. This is the first
application of the energy test in four-body decays. The search is performed for
-even asymmetries and, for the first time, is extended to probe the
-odd case. Using proton-proton collision data corresponding to an integrated
luminosity of 3.0 fb collected by the LHCb detector at centre-of-mass
energies of 7 TeV and 8 TeV, the world's best sensitivity to
violation in this decay is obtained. The data are found to be consistent with
the hypothesis of symmetry with a -value of in the
-even case, and marginally consistent with a -value of in
the -odd case, corresponding to a significance for non-conservation of
2.7 standard deviations.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-044.htm
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