Rediscovering Tandem Repeat Variation in Schizophrenia: Challenges and Opportunities

Tandem repeats (TRs) are prevalent throughout the genome, constituting at least 3% of the genome, and often highly polymorphic. The high mutation rate of TRs, which can be orders of magnitude higher than single-nucleotide polymorphisms and indels, indicates that they are likely to make significant contributions to phenotypic variation, yet their contribution to schizophrenia has been largely ignored by recent genome-wide association studies (GWAS). Tandem repeat expansions are already known causative factors for over 50 disorders, while common tandem repeat variation is increasingly being identified as significantly associated with complex disease and gene regulation. The current review summarizes key background concepts of tandem repeat variation as pertains to disease risk, elucidating their potential for schizophrenia association. An overview of next-generation sequencing-based methods that may be applied for TR genome-wide identification is provided, and some key methodological challenges in TR analyses are delineated.