مجال
التميز
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تميز دراسي وبحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Mutation Intolerant Genes and Targets of FMRP are
Enriched for Nonsynonymous Alleles in Schizophrenia
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رابط إلى البحث:
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Click Here
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تاريخ النشر:
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19/04/2017
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موجز عن البحث:
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Background
Risk of schizophrenia is conferred by alleles
occurring across the full spectrum of frequencies from common SNPs of weak
effect through to ultra-rare alleles, some of which may be moderately to
highly penetrant. Previous studies have suggested that some of the risk of
schizophrenia is attributable to uncommon alleles represented on Illumina
exome arrays.
Methods
Here, we present the largest study of exomic
variation in schizophrenia to date, using samples from the UK and Sweden
(10,011 schizophrenia cases and 13,791 controls). Single variants, genes and
gene sets were analysed for association with schizophrenia.
Results
No single variant or gene reached genome-wide
significance. Among candidate gene sets, we found significant enrichment for
rare alleles (MAF<0.001) in genes intolerant of loss-of-function variation
and in genes whose messenger RNAs bind to FMRP.
Conclusions
We further delineate the genetic architecture of
schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥0.001)
that confer a relatively large effect (OR>4). We also show risk alleles
within this frequency range exist, but confer smaller effects and should be
identified by larger studies.
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البحث (2):
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عنوان البحث:
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Rare Variant Analysis In
Multiply Affected Families, Association Studies And Functional Analysis
Suggest A Role For The ITGΒ4 Gene In Schizophrenia And
Bipolar Disorder
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رابط إلى البحث:
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here
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تاريخ النشر:
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09/03/2018
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موجز عن البحث:
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Background: Recent results imply that rare variants contribute to
the risk of schizophrenia. Exome sequence data from the UK10K project
was used to identify three rare, amino acid changing variants in the ITGB4
gene which segregated with schizophrenia in two families: rs750367954,
rs147480547 and rs145976111. Association analysis was carried out in the
exome-sequenced Swedish schizophrenia study and in UCL schizophrenia and
bipolar cases and controls genotyped for these variants. A gene-wise weighted
burden test was performed on a trio sample of schizophrenia cases and their
parents. rs750367954 was seen in two Swedish cases and in no controls. The other
two variants were commoner in cases than controls in both Swedish and UCL
cohort samples and an overall burden test was significant at p = 0.0000031.
The variants were not observed in the trio sample but ITGB4 was most highly
ranked out of 14,960 autosomal genes in a gene-wise weighted burden test. The
effect of rs147480547 and rs145976111 was studied in human neuroblastoma
SH-SY5Y cells. Cells transfected with both variants had increased
proliferation at both 24 and 48 h (p= 0.013 and p = 0.05 respectively)
compared to thosewithwild-type ITGB4. Taken together, these results suggest
that rare variants in ITGB4which affect function may contribute to the
aetiology of schizophrenia and bipolar disorder.
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البحث (3):
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عنوان البحث:
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Exome Sequence Analysis And
Follow Up Genotyping Implicates Rare ULK1 Variants To Be Involved In
Susceptibility To Schizophrenia
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رابط إلى البحث:
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Click here
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تاريخ النشر:
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17/11/2017
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موجز عن البحث:
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Schizophrenia
(SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the
genetic architecture of the disorder will facilitate greater understanding of
the altered underlying neurobiological mechanisms. The aim of this study was
to identify likely aetiological variants in subjects affected with SCZ.
Exome
sequence data from a SCZ cas–control sample from Sweden was analysed for
likely aetiological variants using a weighted burden test. Suggestive
evidence implicated the UNC-51-like kinase (ULK1) gene, and it was
observed that four rare variants that were more common in the Swedish SCZ
cases were also more common in UK10K SCZ cases, as compared to obesity cases.
These three missense variants and one intronic variant were genotyped in the
University College London cohort of 1304 SCZ cases and 1348 ethnically
matched controls.
All four
variants were more common in the SCZ cases than controls and combining them
produced a result significant at P = 0.02.
The results
presented here demonstrate the importance of following up exome sequencing
studies using additional datasets. The roles of ULK1 in autophagy and
mTOR signalling strengthen the case that these pathways may be important in
the pathophysiology of SCZ. The findings reported here await independent
replication.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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29th ECNP Congress
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تاريخ الإنعقاد:
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17-20 September 2016
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مكان الإنعقاد:
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Vienna, Austria
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Potential involvement of a CLSTN3 variant in
susceptibility to schizophrenia
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ملخص المشاركة:
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Objectives: analysing sequencing data from different
studies to identify rare genetic involvement in Schizophrenia (SCZ). SZC
known to be a disabling severe psychiatric illness, with estimates
heritability up to 80%. This been applied to understand the genetic behind
the disease and there role in disease etiology using SCZ family study.
Methodology: Twenty families from UCL, DNA
polymorphism in mental health (DPIM) study of multiply affected with SCZ were
exome sequenced as part of the UK10K sequencing project. The data were
analyses using bioinformatics tools (GeneSAOcs) and validated using Sorting
Intolerance From Tolerance (SIFT) and PolyPhen2. A rare variant with
potentially associated with SCZ been identified in one of our family in
Calsyntenin 3 (CLSTN3) gene the variant (rs138370117) found only in the
effected members. This variant has been genotyped in UCL samples using KSPR
assay.
Results: a heterozygous variant identified in 2 out
of 1261 SCZ cases and in one control out of 1321 (p=0.473) and did not
appear in any of 1836 bipolar disorder(BPD) cases with p value(0.416)
combining both SCZ and BPD cases/controls p=0.2487. Another set of data have
been investigated using whole exome sequencing data (WES) of 125 SCZ
individuals for this variant and the mutation not been found in any of them.
Combining the analysis for all SCZ case/control gives an odd ratio (odd)
=3.508, (0.758-16.242), chi-square =2.9331 and p value (0.0713).
Conclusion: Although this SNP obtained from SCZ
family study we genotyped it in BPD samples to look for association with
psychosis. The result did not show any association in the BPD sample thus
possibly indicating that this SNP is involved in other factors related to
SCZ. This variant was found in 8 cases out of 5316 patients with SCZ and in 2
out of 4847 controls. Given that this variant is rare the result need to be
validated by looking into other SCZ cases and control cohorts might give an
insight about the role of this SNP in SCZ. And since it been reported that
this gene is associated with autism looking in to autism cohort might give
support evidence of shared variant between SCZ and autism.
Keywords: schizophrenia, CLSTN3 ,Bipolar disorder, association
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المؤتمر (2):
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عنوان المؤتمر:
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The European Human Genetics
Conference 2017
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تاريخ الإنعقاد:
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27-30 May 2017
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مكان الإنعقاد:
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Copenhagen, Denmark
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Genetic
And Functional Association Of Rs61749465 With Bipolar Disorder And
Schizophrenia
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ملخص المشاركة:
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The
microcephalin 1 gene (MCPH1) plays an important role in DNA damage repair and
cell cycle arrest. A low frequency MCPH1 variant rs61749465 A>G
(p.Asp61Gly) showed evidence for association with schizophrenia (SCZ).
We further tested this variant for association in 2,300 bipolar disorder
(BPD) participants, 1,930 SCZ participants and 1,820 normal comparison
subjects and report evidence for association with BPD (P=0.0009).
Notably the variant allele of rs61749465 was absent in the 1,820 comparison subjects
tested. rs61749465 is located in the N-terminal of the BRCT1 domain of
MCPH1. Bioinformatic analysis predicted the Asp61Gly substitution to be
damaging to MCPH1 protein function. A second MCPH1 BRCT1 domain variant
(rs199422124 C>G; p.Thr27Arg), reported to cause autosomal recessive
microcephaly, was also genotyped. This was not detected in any of the
participants tested here.
We
sought to characterize the functional effects of these variants on MCPH1
function. Cell viability and cell count assays indicated that the
variant allele of rs199422124 had a larger impact on cell survival compared
to the variant allele of rs61749465, however neither of the variant alleles
significantly altered DNA damage or mRNA stability. Gene expression analysis
using RNA-seq combined with gene network and pathway analysis indicated that
the variant alleles may impact cellular aging and protein translation.
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