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Genetic modifiers in rare disorders : the case of fragile X syndrome
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Crawford, Hayley, Scerif, Gaia, Wilde, Lucy, Beggs, Andrew, Stockton, Joanne , Sandhu, Pria, Shelley, Lauren, Oliver, Chris and McCleery, Joseph P. (2020) Genetic modifiers in rare disorders : the case of fragile X syndrome. European Journal of Human Genetics . doi:10.1038/s41431-020-00711-x ISSN 1018-4813.
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Official URL: https://doi.org/10.1038/s41431-020-00711-x
Abstract
Methods employed in genome-wide association studies are not feasible ways to explore genotype–phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficit-hyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations.
Item Type: | Journal Article | |||||||||||||||
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Subjects: | R Medicine > RC Internal medicine R Medicine > RJ Pediatrics |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Mental Health and Wellbeing Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Rare diseases, Genetic markers -- Research, Fragile X syndrome | |||||||||||||||
Journal or Publication Title: | European Journal of Human Genetics | |||||||||||||||
Publisher: | Nature Publishing Group | |||||||||||||||
ISSN: | 1018-4813 | |||||||||||||||
Official Date: | 29 August 2020 | |||||||||||||||
Dates: |
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DOI: | 10.1038/s41431-020-00711-x | |||||||||||||||
Status: | Peer Reviewed | |||||||||||||||
Publication Status: | Published | |||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
Date of first compliant deposit: | 14 August 2020 | |||||||||||||||
Date of first compliant Open Access: | 8 October 2020 | |||||||||||||||
RIOXX Funder/Project Grant: |
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