NELL-1 in Genome-Wide Association Studies across Human Diseases

Abstract

Neural epidermal growth factor-like (EGFL)-like protein (NELL)-1 is a potent and key osteogenic factor in the development and regeneration of skeletal tissues. Intriguingly, accumulative data from genome-wide association studies (GWASs) have started unveiling potential broader roles of NELL-1 beyond its functions in bone and cartilage. With exploration of the genetic variants of the entire genome in large-scale disease cohorts, GWASs have been used for establishing the connection between specific single-nucleotide polymorphisms of NELL1, in addition to osteoporosis, metabolic diseases, inflammatory conditions, neuropsychiatric diseases, neurodegenerative disorders, and malignant tumors. This review summarizes the findings from GWASs on the manifestation, significance level, implications on function, and correlation of specific NELL1 single-nucleotide polymorphisms in various disorders in humans. By offering a unique and comprehensive correlation between genetic variants and plausible functions of NELL1 in GWASs, this review illustrates the wide range of potential effects of a single gene on the pathogenesis of multiple disorders in humans.

Figure 1

NELL1-related susceptible gene loci in human disorders. Boxed region indicates the region of NELL1 gene on chromosome 11. IBD, inflammatory bowel disease; NSCLC, non–small cell lung cancer; TG, triglyceride.

Figure 2

Functional validation of candidate SNPs. For candidate SNPs of statistical significance revealed by GWASs, further bioinformatics analysis is applied to categorize them as coding or noncoding. Usually, a combination of multiple servers (more than three) with complementary algorithms was used to minimize errors. In the GWASs in the literature, up to 88% of the SNPs screened are noncoding. Coding SNPs were subclassified as nonsynonymous mutations, in which the amino acid and consequently the encoded protein is changed, and synonymous mutations. While nonsynonymous SNPs could have a direct impact on the protein structure, synonymous SNPs could lead to alternative splicing, or limit the speed of the translation. Noncoding SNPs can also be called regulatory SNPs, which can be located in the promoter, enhancer, 5′-untranslated region (UTR), 3′-UTR, or intronic region. First, GWAS, linkage analysis, and quantitative trait locus mapping are frequently used to detect causal regulatory SNPs. Then, functional testing can be applied to determine the role of targeted SNPs to be transcription-factor binding, chromatin state maintenance, epigenetic modification, or alternative splicing. The general framework of functional validation of noncoding SNPs is suggested elsewhere.

Figure 3

Human disorders with NELL1 manifestation in GWASs.