What's next after the exciting discovery and reassuring replications of genome-wide association studies of restless legs syndrome?

摘要

Two previous consecutive genome-wide association studies (GWASs) have identified and confirmed four genomic regions significantly associated with restless legs syndrome (RLS) in German, Austrian, and French-Canadian case-control samples [1,2]. These four candidate regions include the MEIS1 gene on chromosome 2p, the BTBD9 gene on chromosome 6p, the overlapped region between the MAP2K5 and SKOR1 genes on chromosome 15q, and the PTPRD gene on chromosome 9p. Most recently, a third extended GWAS of RLS has reconfirmed the same allelic associations of these previously reported common variants with RLS in more diverse Caucasian populations from Europe and North America, in addition to the detection of two new loci in much larger German and Austrian samples, i.e., an intergenic region on chromosome 2pl4 (1.3 Mb downstream of the MEIS1 gene) and a locus on 16ql2.1 (close to the TOX3 gene and the non-coding RNA BC034767) [3]. Altogether, the common variants from these six genomic loci, consistently detected in the RLS GWASs [1-4], and confirmed in the concurrent [1-3] and subsequent independent replication studies [5-8], confer small to modest relative risks to RLS (OR: 1.2-1.8), and could give rise to a maximum area under the curve (AUC) of 0.65 for the receiver operator characteristic (ROC), based on a weighted risk allele score for genetic risk prediction [3], which is below the threshold (AUC >= 0.75) as a useful clinical diagnostic classifier when applied to at-risk individuals, e.g., family members of RLS patients [9], Furthermore, common variants from these six RLS-associated loci could only explain 6.8% of the total genetic variance [3], Therefore, the majority of the RLS heritability estimated from previous twin and family studies [10-12] is still missing and/ or hidden. The fact that the common variants detected through GWASs do not explain all the heritability is not a unique situation for RLS but rather a general phenomenon for most of the GWASs of complex dis...