Integrating functional scoring and regulatory data to predict the effect of non-coding SNPs in a complex neurological disease

• Published in: Briefings in functional genomics 2024-03, Vol.23 (2), p.138-149
• Main Authors: Felício, Daniela, Alves-Ferreira, Miguel, Santos, Mariana, Quintas, Marlene, Lopes, Alexandra M, Lemos, Carolina, Pinto, Nádia, Martins, Sandra
• Format: Article
• Language: English
• Subjects: Gene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeodomain Proteins; Humans; Migraine Disorders; Polymorphism, Single Nucleotide - genetics; Regulatory Sequences, Nucleic Acid - genetics; Transcription Factors
• ISSN: 2041-2649; 2041-2657
• DOI: 10.1093/bfgp/elad020

Most SNPs associated with complex diseases seem to lie in non-coding regions of the genome; however, their contribution to gene expression and disease phenotype remains poorly understood. Here, we established a workflow to provide assistance in prioritising the functional relevance of non-coding SNPs of candidate genes as susceptibility loci in polygenic neurological disorders. To illustrate the applicability of our workflow, we considered the multifactorial disorder migraine as a model to follow our step-by-step approach. We annotated the overlap of selected SNPs with regulatory elements and assessed their potential impact on gene expression based on publicly available prediction algorithms and functional genomics information. Some migraine risk loci have been hypothesised to reside in non-coding regions and to be implicated in the neurotransmission pathway. In this study, we used a set of 22 non-coding SNPs from neurotransmission and synaptic machinery-related genes previously suggested to be involved in migraine susceptibility based on our candidate gene association studies. After prioritising these SNPs, we focused on non-reported ones that demonstrated high regulatory potential: (1) VAMP2_rs1150 (3' UTR) was predicted as a target of hsa-mir-5010-3p miRNA, possibly disrupting its own gene expression; (2) STX1A_rs6951030 (proximal enhancer) may affect the binding affinity of zinc-finger transcription factors (namely ZNF423) and disturb TBL2 gene expression; and (3) SNAP25_rs2327264 (distal enhancer) expected to be in a binding site of ONECUT2 transcription factor. This study demonstrated the applicability of our practical workflow to facilitate the prioritisation of potentially relevant non-coding SNPs and predict their functional impact in multifactorial neurological diseases.