Association of Dual <i>LRRK2 </i>G2019S and <i>GBA</i> Variations With Parkinson Disease Progression
Authors: Roberto A. Ortega, Cuiling Wang, Deborah Raymond, Nicole Bryant, Clemens R. Scherzer, Avner Thaler, Roy N. Alcalay, Andrew B. West, Anat Mirelman, Yuliya Kuras, Karen S. Marder, Nir Giladi, Laurie J. Ozelius, Susan B. Bressman, Rachel Saunders-Pullman
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Despite a hypothesis that harboring a leucine-rich repeat kinase 2(<i>LRRK2</i>) G2019S variation and a glucocerebrosidase (<i>GBA</i>) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual<i>LRRK2</i>and<i>GBA</i>variations Parkinson disease (PD) than in<i>GBA</i>variation PD alone. <h3>Objective</h3> To evaluate the association of<i>LRRK2</i>G2019S and<i>GBA</i>variants with longitudinal cognitive and motor decline in PD. <h3>Design, Setting, and Participants</h3> This longitudinal cohort study of continuous measures in<i>LRRK2</i>PD,<i>GBA</i>PD,<i>LRRK2</i>/<i>GBA</i>PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-<i>LRRK2</i>-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for<i>GBA</i>and<i>LRRK2</i>variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020. <h3>Main Outcomes and Measures</h3> The associations of<i>LRRK2</i>G2019S and<i>GBA</i>genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale–Part III scores were examined using linear mixed effects models with PD duration as the time scale. <h3>Results</h3> Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had<i>GBA</i>PD, 155 (13.0%) had<i>LRRK2</i>PD, 21 (1.8%) had<i>LRRK2</i>/<i>GBA</i>PD, and 889 (74.5%) had idiopathic PD. Patients with<i>GBA</i>PD had faster decline in MoCA than those with<i>LRRK2</i>/<i>GBA</i>PD (B [SE], −0.31 [0.09] points/y;<i>P</i> &lt; .001),<i>LRRK2</i>PD (B [SE], −0.33 [0.09] points/y;<i>P</i> &lt; .001), or idiopathic PD (B [SE], −0.23 [0.08] points/y;<i>P</i> = .005). There was a<i>LRRK2</i>G2019S × <i>GBA</i>interaction in MoCA decline (B [SE], 0.22 [0.11] points/y;<i>P</i> = .04), but not after excluding severe<i>GBA</i>variations (B [SE], 0.12 [0.11] points/y;<i>P</i> = .28). Patients with<i>GBA</i>PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y;<i>P</i> = .03) or<i>LRRK2</i>PD (B [SE], 0.77 [0.26] points/y;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> These findings suggest that longitudinal cognitive decline in patients with<i>GBA</i>PD was more severe than in those with<i>LRRK2</i>/<i>GBA</i>PD, which more closely resembled<i>LRRK2</i>PD. This further supports the notion of a dominant association of<i>LRRK2</i>on<i>GBA</i>in individuals who carry both and raises the possibility of an<i>LRRK2</i> × <i>GBA</i>interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe<i>GBA</i>variation is warranted.