Genetic modifiers in rare disorders: the case of fragile X syndrome

Hayley Crawford, Gaia Scerif, Lucy Wilde, Andrew Beggs, Joanne Stockton, Pria Sandhu, Lauren Shelley, Chris Oliver, Joseph McCleery

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2 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)173–183
Number of pages11
JournalEuropean Journal of Human Genetics
Issue number1
Early online date29 Aug 2020
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
Funding Funding for the study was obtained from Coventry University and from Cerebra. HC’s research is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. AB is funded by a Cancer Research UK Advanced Clinician Scientist Award (C31641/A23923).

Publisher Copyright:
© 2020, The Author(s).

Copyright 2020 Elsevier B.V., All rights reserved.


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