Biology subjects

Tammimies, K.

Publications and source records attributed to Tammimies, K..

3 recordsLinked to original sources

bioRxiv2018

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Challenges in social communication and interaction are core symptoms in autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest but heterogeneous effects in clinical trials, and therefore identification of effect moderators could enable more precise intervention decisions. One of the major genetic risk factors in ASD are rare copy number variation (CNV). However, limited information exists whether rare CNVs profiles can be used to aid in intervention decisions. Therefore, we conducted the first study to date analyzing rare CNVs as genetic moderators in the outcome of SSGT in ASD. For this, we analyzed rare genic CNV carrier status of 207 children of which 105 received SSGT and 102 standard care as part of a recent randomized clinical trial for 12-weeks SSGT. We used mixed linear models to assess the association of being a CNV carrier, grouped by the effect and size of the CNVs and the primary response to SSGT, the parent-report Social Responsiveness Scale (SRS) measured at post-intervention and 3-months follow-up. Additionally, we analyzed the secondary outcome assessments included parent-rated adaptive behaviors (ABAS-II) and trainer-rated clinical global impression (CGI). We show that being a carrier of any size rare genic CNV did not impact on the SSGT outcome. However, when stratifying the groups by size of the CNVs, we identified that carriers of large CNVs (>500 kb) showed inferior SRS outcomes at post-intervention ({beta} = 15.35, 95% CI 2.86-27.84, P=0.017) and follow-up ({beta} = 14.19, 95% CI 1.68-26.70, P=0.028). Similar results were shown for the parent-rated secondary outcome. In contrast, the carriers of small CNVs had better outcome at post-intervention ({beta} = -1.20, 95 % CI - 2.0 - -0.4 P = 0.003) but not at follow-up for the trainer-rated secondary outcome CGI. These results remained when we tested the specificity of the effect by including the standard care group and adjusting for IQ levels. While our study suggests that being a carrier of any size rare genic CNV did not impact the outcome, it provides preliminary evidence that carriers of high-risk CNVs might not benefit on SSGT as much as non-carriers. Our results indicate that genetic information eventually might help guide personalized intervention planning in ASD. We additionally highlight that more research is needed to understand the intervention needs of autistic individuals with specified molecular alterations.

genetics↗

bioRxiv2017

Copy number variation and neurodevelopmental problems in females and males in the general population

ObjectiveNeurodevelopmental problems (NPs) are childhood phenotypes that are more common in males. Conversely, anxiety and depression (which are frequently comorbid with NPs) are more common in females. Rare copy number variants (CNVs) have been implicated in clinically-defined NPs. Here, we aimed to characterise the relationship between rare CNVs with NPs and anxiety/depression in a population sample of twin children. Additionally, we examined whether sex-specific CNV effects underlie the sex bias of these disorders.\n\nMethodWe analysed a sample of N=12,982 children, of whom 5.3% had narrowly-defined NPs (clinically-diagnosed), 20.9% had broadly-defined NPs (based on validated screening measures, but no diagnosis) and 3.0% had clinically-diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorised by size (medium: 100-500kb or large: >500kb), type (duplication or deletion) and putative relevance to NPs (affecting previously implicated loci or evolutionarily-constrained genes). We tested for associations between the different CNV categories with NPs and anxiety/depression, followed by examination of sex-specific effects.\n\nResultsMedium deletions (OR(CI)=1.18(1.05-1.33),p=0.0053) and large duplications (OR(CI)=1.45(1.19-1.75),p=0.00017) were associated with broadly-defined NPs. Large deletions (OR(CI)=1.85(1.14-3.01),p=0.013) were associated with narrowly-defined NPs. The effect sizes increased for large NP-relevant CNVs (broadly-defined: OR(CI)=1.60(1.06-2.42),p=0.025; narrowly-defined: OR(CI)=3.64(2.16-6.13),p=1.2E-6). No sex differences in CNV burden were found in individuals with NPs (p>0.05). In individuals diagnosed with anxiety or depression, females were more likely to have large CNVs (OR(CI)=3.75(1.45-9.68),p=0.0064).\n\nConclusionRare CNVs are significantly associated with both narrowly- and broadly-defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.

genetics↗

bioRxiv2017

Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

genetics↗