Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (<i>SSTR5</i>) gene in patients with autism

Lauritsen, Marlene Briciet; Nyegaard, Mette; Betancur, Catalina; Colineaux, Catherine; Josiassen, Trine L.; Kruse, Torben A.; Leboyer, Marion; Ewald, Henrik

doi:10.1002/ajmg.b.20050

Cited by 7 publications

(4 citation statements)

References 31 publications

(29 reference statements)

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“…These data represent one of the more significant association between a candidate gene and ASD in the publicly available AGRE data set (www.agre.org). [52][53][54][55][56][57][58][59][60][61] The triad data also define a minimal population for future family-based association studies that is both a powerful and cost-efficient alternative to using extended nuclear families.…”

Section: Discussionmentioning

confidence: 99%

Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder

et al. 2004

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Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic individuals display similar cerebellar morphological abnormalities, which include hypoplasia and a decrease in the number of Purkinje cells. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Human EN2 maps to 7q36, a chromosomal region that has demonstrated suggestive linkage to autism spectrum disorder (ASD). [20][21][22] To investigate EN2 for evidence of association with ASD, four single-nucleotide polymorphisms (SNPs) (rs3735653, rs1861972, rs1861973, rs2361689) that span the majority of the 8.0 kb gene were assessed by the transmission/disequilibrium test [23][24][25][26] . Initially, 138 triads of autistic individuals and their parents were tested. Two intronic SNPs (rs1861972 and rs1861973) demonstrated significant association with autism (rs1861972, P ¼ 0.0018; rs1861973, P ¼ 0.0003; haplotype, P ¼ 0.000005). Flanking exonic SNPs (rs3735653 and rs2361689) did not display association. This analysis was then extended to include 167 small nuclear ASD pedigrees and significant association was again only observed for rs1861972 and rs1861973 under both the narrow and broad diagnostic criteria (narrow: rs1861972 P ¼ 0.0290, rs1861973 P ¼ 0.0073, haplotype P ¼ 0.0009; broad: rs1861972 P ¼ 0.0175, rs1861973 P ¼ 0.0107, haplotype P ¼ 0.0024). These data demonstrate association between a cerebellar patterning gene and ASD, suggesting a role for EN2 as a susceptibility locus and supporting a neurodevelopmental defect hypothesis in the etiology of autism.

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Section: Discussionmentioning

confidence: 99%

Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder

et al. 2004

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“…Unfortunately, the rs34037914 and rs642249 were not genotyped in a study performed Filopanty et al . (16) The C allele of the rs169068 was associated with the presence of bipolar affective disorder in a British but not in a Danish population (24), while there was a lack of association with autism in both Danish and French populations (25). No association was found between this SNP and risk or survival of pancreatic cancer (26).…”

Section: Discussionmentioning

confidence: 99%

Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly

Ciganoka

Balcere²,

Kāpa³

et al. 2011

European Journal of Endocrinology

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ObjectiveThe aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics.Design and methodsThe SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls.ResultsIn total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR)=3.38; 95% confidence interval (CI), 1.78–6.42; P=0.00016 and OR=2.41; 95% CI, 1.41–4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P<0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient β=−10.4; P=0.002), increased body mass index (β=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014).ConclusionsOur results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.

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“…A primate-specific single nucleotide polymorphism (SNP) in the human somatostatin gene [C/T polymorphism (rs4988514)] is associated with increased risk in Alzheimer’s disease progression and additive effect with the APOE epsilon4 allele(Vepsalainen et al, 2007; Xue et al, 2009), although this was not confirmed in larger genome-wide association studies (GWAS) (Hollingworth et al, 2011; Guerreiro et al, 2013). Leu48Met and Pro335Leu SNPs in the SST5 gene are of potential significance to patients with bipolar disorder (Nyegaard et al, 2002), but no associations of SST5 SNPs are found in patients with autism (Lauritsen et al, 2003). The paucity of associations with somatostatin gene variants is surprising and may reflect either strong negative selection against genetic variations in this gene, or alternatively, dilution of signal due to heterogeneity of DSM-IV-based cohorts in genetic association studies.…”

Section: Somatostatin: Genes Neurons and Pharmacologymentioning

confidence: 99%

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

2013

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Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders.

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Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

Cited by 7 publications

References 31 publications

Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder

Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder

Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

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