MAO-B Polymorphism Associated with Progression in a Chinese Parkinson’s Disease Cohort but Not in the PPMI Cohort

Abstract

Introduction Genetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods PD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression. Results In the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients. Conclusion MAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

Genetic Insights into the Molecular Pathophysiology of Depression in Parkinson’s Disease

“…In addition to dopamine, MAO-B also degrades norepinephrine, which is implicated in several physiological functions, including cognition, pain, sleep, and emotional processing. Hence, MAO-B could mediate the pathophysiological mechanisms underlying the non-motor symptoms in PD, such as depression [ 8 ]. Recently, a study of PD patients from China and the Parkinson’s Progression Markers Initiative (PPMI) cohort has indicated that although the MAOB rs1799836 polymorphism was linked to the progression of non-motor symptoms of the patients in general in the Chinese cohort, there was no specific association with the progression of depression or anxiety in both cohorts [ 8 ].…”

“…Hence, MAO-B could mediate the pathophysiological mechanisms underlying the non-motor symptoms in PD, such as depression [ 8 ]. Recently, a study of PD patients from China and the Parkinson’s Progression Markers Initiative (PPMI) cohort has indicated that although the MAOB rs1799836 polymorphism was linked to the progression of non-motor symptoms of the patients in general in the Chinese cohort, there was no specific association with the progression of depression or anxiety in both cohorts [ 8 ]. Hence, the MAOA and MAOB gene polymorphisms seem not to significantly affect depression in PD patients.…”

“…In particular, PARK16 polymorphisms, such as RAB29 and NUCKS1, have been associated with a lower risk of PD in the Caucasian and Asian population [ 125 ]. A recent study has demonstrated that the progression of anxiety and depressive symptoms in PD patients was associated with the PARK16 haplotype in a sample from the PPMI cohort [ 8 ], although the molecular mechanisms remain unclear.…”

“…Mendelian-inherited monogenic familial forms of PD constitute only 5–10% of all cases [ 6 ], including mutations in the LRRK2 , SNCA , Parkin , PINK1 , DJ1, ATP13A2 , VPS35 , and GBA1 genes, which are inherited in a dominant or recessive manner [ 7 ]. Additionally, genome-wide association studies (GWAS) have revealed at least ninety independent genetic loci that may affect the susceptibility to sporadic PD, overall contributing to an estimated heritability of 22–27% [ 8 ]. PD represents a clinically heterogeneous disorder and there is a growing interest in the elucidation of the genetic contribution to this diversity [ 9 , 10 ].…”