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

Research output: Contribution to journalArticle


  • Hayley Crawford
  • Gaia Scerif
  • Pria Sandhu
  • Lauren Shelley
  • Joseph McCleery

Colleges, School and Institutes

External organisations

  • Faculty of Health and Life Sciences
  • Warwickshire, Solihull and Coventry Breast Screening Service, University Hospitals Coventry and Warwickshire, Coventry, United Kingdom.
  • Warwick Medical School, University of Warwick
  • University of Warwick Library, University of Warwick
  • Cerebra Centre for Neurodevelopmental Disorders
  • Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Oncology, University of Oxford, Oxford, UK.
  • The Open University
  • Rheumatology Department, Milton Keynes University Hospital, Milton Keynes.
  • Surgical Research Laboratory, Institute of Cancer & Genomic Science, University of Birmingham, UK.
  • Institute of Cancer and Genomic Sciences
  • University of Birmingham Microbiome Treatment Centre, University of Birmingham, Birmingham, United Kingdom; Department of Gastroenterology, University Hospital Birmingham, Birmingham, United Kingdom. Electronic address:
  • Saint Joseph's University


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
JournalEuropean Journal of Human Genetics
Publication statusE-pub ahead of print - 29 Aug 2020