CAG repeat polymorphism within the <i>KCNN3</i> gene is a significant contributor to susceptibility to anorexia nervosa: A case‐control study of female patients and several ethnic groups in the Israeli Jewish population

Koronyo‐Hamaoui, Maya; Gak, Eva; Stein, Dan J.; Frisch, Amos; Danziger, Y; Leor, Shani; Michaelovsky, Elena; Laufer, Neil; Carel, Cynthia A.; Fennig, Silvana; Mimouni, Marc; Apter, Alan; Goldman, Boleslav; Barkai, Gad; Weizman, Abraham

doi:10.1002/ajmg.b.20154

Cited by 21 publications

(5 citation statements)

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“…SHC1 encodes a signaling and transforming protein that couples various growth factors into the signaling pathway, and is associated with stress responses and increased lifespan in mammals [47]. KCNN3 encodes a small conductance calcium-activated potassium channel that is thought to regulate neuronal excitability, and polymorphisms in KCNN3 have been associated with several neural disorders, including schizophrenia [48]and anorexia nervosa [49]. Another strong signal of selection is associated with a cluster of β-defensin genes that map to the region Chr8: 10917927-11894726.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

et al. 2009

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BackgroundGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.MethodologyWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.ConclusionsOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

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Section: Discussionmentioning

confidence: 99%

Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

et al. 2009

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“…Finally, the top two SNPS located on chromosome 1 are also worth mentioning given that significant over‐representation of KCNN3 alleles with longer CAG repeats have been previously reported in AN patients [Koronyo‐Hamaoui et al, 2002, 2004]. The small‐conductance calcium‐activated potassium channel gene KCNN3 is expressed in brain; increased expression in the hippocampus has been associated with reduced long‐term potentiation [Blank et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

Association study of 182 candidate genes in anorexia nervosa

Pinheiro

Bulik

Thornton

et al. 2010

American J of Med Genetics Pt B

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We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN NIH Public AccessAuthor Manuscript Am J Med Genet B Neuropsychiatr Genet. Author manuscript; available in PMC 2010 October 25. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathwaybased analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.

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“…In our study, NCOA3 lay just below the threshold for priority candidate disease genes, with nine CAG while priority candidates had ten CAG. KCNN3 CAG-tract length differences have been associated with anorexia [78] and with schizophrenia and bipolar disorder but these associations are controversial [79]. SMARCA2 and THAP11 were previously identified as candidates by Pandey [28] based on their relatively long uninterrupted CAG-tracts.…”

Section: Discussionmentioning

confidence: 99%

CAG-encoded polyglutamine length polymorphism in the human genome

et al. 2007

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BackgroundExpansion of polyglutamine-encoding CAG trinucleotide repeats has been identified as the pathogenic mutation in nine different genes associated with neurodegenerative disorders. The majority of individuals clinically diagnosed with spinocerebellar ataxia do not have mutations within known disease genes, and it is likely that additional ataxias or Huntington disease-like disorders will be found to be caused by this common mutational mechanism. We set out to determine the length distributions of CAG-polyglutamine tracts for the entire human genome in a set of healthy individuals in order to characterize the nature of polyglutamine repeat length variation across the human genome, to establish the background against which pathogenic repeat expansions can be detected, and to prioritize candidate genes for repeat expansion disorders.ResultsWe found that repeats, including those in known disease genes, have unique distributions of glutamine tract lengths, as measured by fragment analysis of PCR-amplified repeat regions. This emphasizes the need to characterize each distribution and avoid making generalizations between loci. The best predictors of known disease genes were occurrence of a long CAG-tract uninterrupted by CAA codons in their reference genome sequence, and high glutamine tract length variance in the normal population. We used these parameters to identify eight priority candidate genes for polyglutamine expansion disorders. Twelve CAG-polyglutamine repeats were invariant and these can likely be excluded as candidates. We outline some confusion in the literature about this type of data, difficulties in comparing such data between publications, and its application to studies of disease prevalence in different populations. Analysis of Gene Ontology-based functions of CAG-polyglutamine-containing genes provided a visual framework for interpretation of these genes' functions. All nine known disease genes were involved in DNA-dependent regulation of transcription or in neurogenesis, as were all of the well-characterized priority candidate genes.ConclusionThis publication makes freely available the normal distributions of CAG-polyglutamine repeats in the human genome. Using these background distributions, against which pathogenic expansions can be identified, we have begun screening for mutations in individuals clinically diagnosed with novel forms of spinocerebellar ataxia or Huntington disease-like disorders who do not have identified mutations within the known disease-associated genes.

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CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: A case‐control study of female patients and several ethnic groups in the Israeli Jewish population

Cited by 21 publications

References 35 publications

Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

Association study of 182 candidate genes in anorexia nervosa

CAG-encoded polyglutamine length polymorphism in the human genome

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