Genetic Analysis of the SLC38A6 Gene in Chinese Patients with Essential Tremor: Not Causative, But Rather an Additional Susceptibility Gene?

BACKGROUND: A recent study implicated rare SLC38A6 variants in Han Chinese cases of essential tremor (ET). OBJECTIVES: To validate the association between SLC38A6 and ET in an independent cohort via gene-level burden analysis and family co-segregation. METHODS: We sequenced all coding exons and splice sites of SLC38A6 in 724 Han Chinese ET patients and 606 controls, performing gene-level burden tests and co-segregation analysis. RESULTS: Eleven rare variants were identified. The most recurrent variant, c.323A>T (p.Y108F), was enriched in cases (3.45% vs. 1.16%; odds ratio [OR] 3.06, 95% confidence interval [95% CI] 1.31-7.13, P = 0.0065). Gene-level analysis showed significantly more rare-variant carriers in cases than in controls (7.73% vs. 3.63%; OR 2.23, 95% CI 1.34-3.69, P = 0.0015), confirmed by sequence kernel association test (SKAT) (P = 0.0257). Six of 12 families showed co-segregation of c.323A>T (p.Y108F), c.719C>A (p.P240Q), or c.752A>G (p.Y251C) with ET. CONCLUSIONS: These findings support SLC38A6 as a candidate susceptibility gene for ET in Han Chinese.