<i>GBA</i> variants in REM sleep behavior disorder: A multicenter study.

Abstract

To study the role of <i>GBA</i> variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. <i>GBA</i> was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of <i>GBA</i> variants on the risk of iRBD, age at onset (AAO), and conversion rates. <i>GBA</i> variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; <i>p</i> = 1 × 10^-10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; <i>p</i> = 3.5 × 10^-5), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; <i>p</i> = 0.0015). Carriers of severe <i>GBA</i> variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers (<i>p</i> = 0.029). Of the <i>GBA</i> variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (<i>p</i> = 0.011), with a trend for faster conversion among severe <i>GBA</i> variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution. <i>GBA</i> variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe <i>GBA</i> variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of <i>GBA</i> variants should be studied as a potential way to identify <i>GBA</i> variant carriers who will develop a synucleinopathy in the future.