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Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry.

Sousa I, Clark TG, Holt R, Pagnamenta AT, Mulder EJ, Minderaa RB, Bailey AJ, Battaglia A, Klauck SM, Poustka F, Monaco AP, International Molecular Genetic Study of Autism Consortium (IMGSA - Mol Autism (2010)

Bottom Line: Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches.These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. anthony.monaco@well.ox.ac.uk.

ABSTRACT

Background: Autism spectrum disorders (ASDs) are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR) proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes - LRRTM1 (2p), LRRTM3 (10q), LRRN1 (3p) and LRRN3 (7q) - in order to identify common genetic risk factors underlying ASDs.

Methods: In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls.

Results: Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.

Conclusions: Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

No MeSH data available.


Related in: MedlinePlus

The graphical output from Haploview. The markers tested and the haplotype blocks constructed for (a) LRRN1, (b) LRRN3 and (c) LRRTM3 are included. D' values are indicated (bright red corresponds to D' = 1, with the colour tending towards white as D' tends towards 0).
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Figure 1: The graphical output from Haploview. The markers tested and the haplotype blocks constructed for (a) LRRN1, (b) LRRN3 and (c) LRRTM3 are included. D' values are indicated (bright red corresponds to D' = 1, with the colour tending towards white as D' tends towards 0).

Mentions: The pairwise linkage disequilibrium (LD) maps for LRRN1, LRRN3 and LRRTM3 were constructed from genotypes using the Haploview software (Figure 1). SNP and haplotype association in families was assessed using the transmission disequilibrium test (TDT) [55], with a version robust to non-independent siblings implemented [56], allowing for the use of multiple siblings within a nuclear family. Allele frequencies were reported for all the parents and children. From applying the TDT, the allele transmission frequencies from parents to offspring were also estimated. Parental transmissions were also analysed for each SNP to consider parent-of-origin effects. In order to combine the evidence across all cohorts at each polymorphism, we estimated odds ratios (ORs) and their standard errors from transmission frequencies [57] and then performed a meta-analysis pooling using an inverse variance approach [58]. Also, at each polymorphism we performed a chi-square test of heterogeneity of the ORs [58]. Meta-analysis forest plots were constructed for each marker using the meta library in the R statistical software http://www.r-project.org. A haplotype-based TDT analysis was also carried out using TRANSMIT [56]. For each haplotype, risk estimates and their 95% credibility internals were estimated using a Bayesian method [55,56]. Logistic regression was used in the analysis of both the alleles and genotypes in the case-control study. When we were analysing cases from the same family, we performed a weighted logistic analysis where each family contributed the same weight. In the logistic regression framework, testing on the genotypes (for example, dd, DD and Dd) without regard to any 'order', allelic count or allelic pairing was performed. In particular, we investigated several related genotypic mechanisms: (i) an additive model which assesses the influence of increasing the number of minor alleles (0,1,2) on log-risk; (ii) dominant model (of the 'd' allele: dd/Dd versus DD); (iii) recessive model (of 'd': dd versus Dd/DD); (iv) heterozygous advantage (Dd versus DD/dd); (v) general model (dd versus DD, Dd versus DD). We report the minimum P-value from these correlated tests. Meta-analytic approaches were also applied to pool the resulting allele- and genotype-based ORs across populations.


Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry.

Sousa I, Clark TG, Holt R, Pagnamenta AT, Mulder EJ, Minderaa RB, Bailey AJ, Battaglia A, Klauck SM, Poustka F, Monaco AP, International Molecular Genetic Study of Autism Consortium (IMGSA - Mol Autism (2010)

The graphical output from Haploview. The markers tested and the haplotype blocks constructed for (a) LRRN1, (b) LRRN3 and (c) LRRTM3 are included. D' values are indicated (bright red corresponds to D' = 1, with the colour tending towards white as D' tends towards 0).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913944&req=5

Figure 1: The graphical output from Haploview. The markers tested and the haplotype blocks constructed for (a) LRRN1, (b) LRRN3 and (c) LRRTM3 are included. D' values are indicated (bright red corresponds to D' = 1, with the colour tending towards white as D' tends towards 0).
Mentions: The pairwise linkage disequilibrium (LD) maps for LRRN1, LRRN3 and LRRTM3 were constructed from genotypes using the Haploview software (Figure 1). SNP and haplotype association in families was assessed using the transmission disequilibrium test (TDT) [55], with a version robust to non-independent siblings implemented [56], allowing for the use of multiple siblings within a nuclear family. Allele frequencies were reported for all the parents and children. From applying the TDT, the allele transmission frequencies from parents to offspring were also estimated. Parental transmissions were also analysed for each SNP to consider parent-of-origin effects. In order to combine the evidence across all cohorts at each polymorphism, we estimated odds ratios (ORs) and their standard errors from transmission frequencies [57] and then performed a meta-analysis pooling using an inverse variance approach [58]. Also, at each polymorphism we performed a chi-square test of heterogeneity of the ORs [58]. Meta-analysis forest plots were constructed for each marker using the meta library in the R statistical software http://www.r-project.org. A haplotype-based TDT analysis was also carried out using TRANSMIT [56]. For each haplotype, risk estimates and their 95% credibility internals were estimated using a Bayesian method [55,56]. Logistic regression was used in the analysis of both the alleles and genotypes in the case-control study. When we were analysing cases from the same family, we performed a weighted logistic analysis where each family contributed the same weight. In the logistic regression framework, testing on the genotypes (for example, dd, DD and Dd) without regard to any 'order', allelic count or allelic pairing was performed. In particular, we investigated several related genotypic mechanisms: (i) an additive model which assesses the influence of increasing the number of minor alleles (0,1,2) on log-risk; (ii) dominant model (of the 'd' allele: dd/Dd versus DD); (iii) recessive model (of 'd': dd versus Dd/DD); (iv) heterozygous advantage (Dd versus DD/dd); (v) general model (dd versus DD, Dd versus DD). We report the minimum P-value from these correlated tests. Meta-analytic approaches were also applied to pool the resulting allele- and genotype-based ORs across populations.

Bottom Line: Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches.These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. anthony.monaco@well.ox.ac.uk.

ABSTRACT

Background: Autism spectrum disorders (ASDs) are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR) proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes - LRRTM1 (2p), LRRTM3 (10q), LRRN1 (3p) and LRRN3 (7q) - in order to identify common genetic risk factors underlying ASDs.

Methods: In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls.

Results: Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.

Conclusions: Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

No MeSH data available.


Related in: MedlinePlus