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Träfflista för sökning "WFRF:(Mcgrath Patrick) srt2:(2012)"

Sökning: WFRF:(Mcgrath Patrick) > (2012)

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1.
  • Casey, Jillian P, et al. (författare)
  • A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
  • 2012
  • Ingår i: Human Genetics. - 0340-6717. ; 131:4, s. 565-579
  • Tidskriftsartikel (refereegranskat)abstract
    • Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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2.
  • Friedrich, Felix W., et al. (författare)
  • Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy
  • 2012
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 21:14, s. 3237-3254
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in 40 of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459CA/C153X and c.827GC/C276S). Whereas the c.459CA variant was associated with muscle weakness in some patients, the c.134delA and c.827GC variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
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3.
  • Kristjánsdóttir, Ólöf, et al. (författare)
  • A systematic review of cross-cultural comparison studies of child, parent, and health professional outcomes associated with pediatric medical procedures
  • 2012
  • Ingår i: Journal of Pain. - : Elsevier. - 1526-5900. ; 13:3, s. 207-219
  • Forskningsöversikt (refereegranskat)abstract
    • The purpose of this review was to evaluate systematically all published and unpublished research concerning culture and medical procedural pain in children. Databases, reference lists, and electronic list servers were searched as data sources. Fifteen studies met the inclusion criteria. Most studies (80%) were conducted solely in the United States comparing Caucasian American groups to other local subculture(s) (ie, African American, Hispanic, or Japanese). The studies compared, cross culturally, pediatric pain-related outcomes in children, parents and/or health professionals. The medical procedural experiences included surgery, immunization, spinal tap, bone marrow aspiration, needle procedures, orthopedic, and wound-related injuries. The evidence published to date suggests that cultural factors may be associated with children's pain experiences when elicited by medical procedural pain, specifically children's pain behavior. Nevertheless, research using more sophisticated research methods is needed to develop culturally sensitive behavioral pain measures. Measures that include physiological pain parameters in addition to other behavioral outcomes may be helpful. Culturally comparative research would benefit from the use of theoretical frameworks to advance our understanding of the cultural underpinnings of child pain development and guide future research.PERSPECTIVE:The current evidence supports that children and parents belonging to cultural minority groups, and in need of health care, are a vulnerable population. Together, researchers and clinicians are encouraged to explore this understudied area, and take advantage of sophisticated methods developed by disciplines like cross-cultural psychology.
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