Reassessing GWAS findings for the shared genetic basis of insomnia and restless legs syndrome.

ABSTRACT

Two genome-wide association studies (GWAS) suggest that insomnia and restless legs syndrome (RLS) share a common genetic basis. While the identified genetic variation in the MEIS1 gene was previously associated with RLS, the two GWAS suggest a novel and independent association with insomnia symptoms. To test the potential pleiotropic effect of MEIS1, we genotyped three MEIS1 variants in 646 chronic insomnia disorder (CID) patients with and without RLS. To confirm our results, we compared the allelic and genotypic distributions of the CID cohort with ethnically matched controls and RLS cases in the French Canadian cohort. The CID cohort was diagnosed by sleep medicine specialists and 26% of the sample received the combined diagnosis of CID+RLS. We find significant differences in allele and genotype distributions between CID-only and CID+RLS groups, suggesting that MEIS1 is only associated with RLS. Genotype distributions and minor allele frequencies of the three MEIS1 SNPs of the CID-only and control groups were similar (rs113851554 5.3% vs. 5.6%; rs2300478 25.3% vs. 26.5%; rs12469063 23.6% vs. 24.4%; all p > 0.05). Likewise, there were no differences between CID+RLS and RLS-only groups (all p > 0.05). In conclusion, our data confirms that MEIS1 is a genetic risk factor for the development of RLS, but it does not support the pleiotropic effect of MEIS1 in CID. While a lack of power precluded us from refuting small pleiotropic effects, our findings emphasize the critical importance of isolating CID from other disorders that can cause sleep difficulties, particularly RLS, for future genetic studies.