Ya-qin Wang

C9orf72 mutation is rare in Alzheimer's disease, Parkinson's disease, and essential tremor in China

GGGGCC repeat expansions in the C9orf72 gene have been identified as a major contributing factor in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the overlapping of clinical phenotypes and pathological characteristics between these two diseases and Alzheimers disease (AD), Parkinsons disease (PD), and essential tremor (ET), we speculated regarding whether C9orf72 repeat expansions also play a major role in these three diseases. Using the repeat-primed polymerase chain reaction method, we screened for C9orf72 in three groups of patients with PD (n = 911), AD (n = 279), and ET (n = 152) in the Chinese Han population. There were no pathogenic repeats (>30 repeats) detected in either the patients or controls (n = 314), which indicated that the pathogenic expansions of C9orf72 might be rare in these three diseases. However, the analysis of the association between the number of repeats (p = 0.001), short/intermediate genotype (short: <7 repeats; intermediate: ≥7 repeats) (odds ratio 1.37 [1.05, 1.79]), intermediate/intermediate genotype (Odds ratio 2.03 [1.17, 3.54]), and PD risks indicated that intermediate repeat alleles could act as contributors to PD. To the best of our knowledge, this study is the first to reveal the correlation between C9orf72 and Chinese PD, AD, or ET patients. Additionally, the results of this study suggest the novel idea that the intermediate repeat allele in C9orf72 is most likely a risk factor for PD.

Lower serum UA levels in Parkinson's disease patients in the Chinese population

Parkinsons disease (PD) is the second most common neurodegenerative disease in the world, and oxidative stress plays an important role in its pathogenesis. Uric acid (UA) is a product of purine metabolism and is a natural antioxidant that can relieve the oxidative stress that occurs in PD. Recent studies have indicated that the serum UA level are associated with a risk of PD and PD progression of motor symptoms and have proposed UA as a possible biomarker of the underlying pathophysiology of PD. In our study, we investigated the association between serum UA level and PD in a Chinese population. We found that the serum UA levels in PD patients were lower than the levels in control patients and were correlated with PD progression and duration in the Chinese population. These associations were observed in both genders, but hyperuricemia is more strongly associated with lower rates of PD among men compared to women and older people compared to younger people. Our results indicate that UA could be an important biomarker of PD and that the serum UA level could be a useful biomarker of PD diagnosis and disease progression.

Lack of association between IL-10 and IL-18 gene promoter polymorphisms and Parkinson’s disease with cognitive impairment in a Chinese population

Inflammatory processes have been implicated in the pathogenesis of Parkinson’s disease (PD), including the development of PD-associated cognitive impairment. Whether genetic variants of inflammatory cytokine genes influence the risk of cognitive impairment in PD is unknown. In this study, we investigated single nucleotide polymorphisms (SNPs) in the IL-10 promoter (rs1800871 and rs1800872) and in the IL-18 promoter (rs1946518 and rs187238) in a Han Chinese cohort (N = 933). PD patients (N = 460) and controls (N = 473) were genotyped. Additionally, 268 PD patients were divided into three subgroups [cognitively normal (PD-NC), mild cognitive impairment (PD-MCI), and with dementia (PD-D)] on the basis of their performance on a battery of neuropsychological tests. No associations were found between the aforementioned polymorphisms and cognitive impairment in PD; thus no confirmatory evidence for the hypothesis of IL-10 and IL-18 alleles modulating the risk of cognitive impairment in Chinese PD patients was obtained.

Assessment of RIT2 rs12456492 association with Parkinson's disease in Mainland China

A recent meta-analysis of genome-wide association studies in Parkinsons disease (PD) has identified the rs12456492 variant in RIT2 as a new susceptibility loci. Because the characteristics of this locus in a Han Chinese population from mainland China was still unknown, we performed a case-control replication study in this population and investigated RIT2 rs12456492 variant in a large cohort of Chinese Han individuals. In total, 933 subjects comprising 460 PD patients and 473 control subjects were genotyped. We found a significant difference in the distributions of genotype and allele between PD and control groups (genotype p = 0.008, allele p = 0.007, odds ratio = 1.296, 95% confidence interval = 1.075-1.563). This study replicates the association between rs12456492 variant and risk of developing PD in a Han Chinese population.

A neurophysiological profile in Parkinson’s disease with mild cognitive impairment and dementia in China

Mild cognitive impairment (MCI) and dementia (D) are frequent features of Parkinsons disease (PD) but widely disparate criteria have been used. Our understanding of the prevalence and cognitive profile of Chinese PD patients remains limited. In order to determine the frequency and pattern of cognitive dysfunction and identify risk factors for cognitive dysfunction in the Chinese Han PD population we performed a cross-sectional study in a cohort of 330 PD patients and 163 healthy controls. Five cognitive domains (executive function, attention, praxis and visuospatial function, memory, and language) and mood/behavior were evaluated. According to the Movement Disorder Society Task Force consensus criteria, up to 29.1% of PD patients were classified as PD-MCI and 32.1% as PD-D. Impairments occur in a range of cognitive domains with dysexecutive profile predominating. Healthy controls also outperformed cognitively preserved PD patients in tasks of executive function and attention. Logistic regression indicated that PD-MCI may be predicted by lower educational level and apathy. Additionally, later disease onset, longer disease duration, more severe motor symptoms and higher neuropsychiatric inventory score were associated with a faster transition from PD-MCI to PD-D. These findings suggest that all PD patients should undergo routine cognitive screening. For high-risk patients early recognition and therapeutic intervention is imperative.

The single nucleotide polymorphism Rs12817488 is associated with Parkinson's disease in the Chinese population

A recent meta-analysis of datasets from five of the published Parkinsons disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population.

Analysis of several loci from genome-wide association studies in Parkinson’s disease in mainland China

Large-scale meta-analyses of genome-wide association studies in Parkinsons disease (PD) have identified a number of susceptibility loci in sporadic PD. Since the characteristics of those loci in a Han Chinese population from mainland China were unknown, we performed a case-control replication study in this population and evaluated several single nucleotide polymorphisms (SNPs) identified in a recent GWAS-meta-analysis. In total, 933 subjects comprised of 460 PD patients and 473 controls were genotyped. We found strong evidence of an association for rs708723 in RAB7L1 in the total sample (genotype p=0.01, allele p=0.01, OR=0.78, 95% CI=0.65-0.94). With rs156429 in GPNMB, there was a significant difference in genotype and allele distribution between male PD patients and the control subgroup (genotype p=0.01, allele p=0.01, OR=0.67, 95% CI=0.49-0.92). However, we did not observe any significant difference in genotype or allele distribution between PD and control for rs34016896 in NMD3 and rs6812193 in STBD1.

Relationship between Alzheimer's disease GWAS-linked top hits and risk of Parkinson's disease with or without cognitive decline: a Chinese population-based study

Alzheimers disease (AD), Parkinsons disease (PD), and cognitive impairment in PD have overlapping clinical and pathological features. To examine whether there is a genetic link for these diseases, we performed a case-control study in Chinese population to evaluate the association of AD genome-wide association studies top hits with both PD and cognitive function in PD, investigating 13 single-nucleotide polymorphisms in 9 genes (BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP). A total of 454 controls and 442 PD patients were genotyped, including 75 mild cognitive impairment and 99 dementia. As a result, no significant association of the AD-susceptibility loci was identified in PD cases, PD-dementia, or PD-mild cognitive impairment. Our findings imply that the 13 single-nucleotide polymorphisms from AD genome-wide association studies may not play major role in the genetic predisposition with PD and cognitive function in PD in a Chinese population.

Association analysis of STK39, MCCC1/LAMP3 and sporadic PD in the Chinese Han population

With the completion of the Human Genome Project, GWAS have been widely used in exploring the genetic studies of complex diseases. A meta-analysis of datasets from five Parkinsons disease GWAS from the USA and Europe found 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)), and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11 and CCDC62/HIP1R). Another GWAS of the Ashkenazi Jewish population also identified loci in STK39 and LAMP3. Because the association between the STK39 and MCCC1/LAMP3 genes and PD was confirmed in different populations, we conducted a case-control cohort to clarify the association between the four single nucleotide polymorphism (SNP) loci (rs2102808 and rs3754775 in the STK39; rs11711441 and rs12493050 in the MCCC1/LAMP3) and PD in the Chinese Han population. Polymerase chain reaction and direct DNA sequencing analyses were used to detect the four variations in a case-control cohort comprised of 993 ethnic Chinese subjects. We found that in the detection of the rs11711441, there was a significant difference between ungrouped populations, early-onset PD, late-onset PD, male PD, female PD and the corresponding control group in allele and genotype frequency (p<0.001, OR<1). In the detection of the rs2102808, rs3754775 and rs12493050, ungrouped populations, early-onset PD, late-onset PD, male PD or female PD with the corresponding control group showed no significant difference in allele and genotype frequency (p>0.0125). Our findings suggested that the allele G of rs11711441 of the MCCC1/LAMP3 gene can decrease the risk of PD in Chinese population. No statistically significant difference in genotype frequency between cases and controls was observed for the other three SNPs.

Mutation Detection in Candidate Genes for Benign Familial Infantile Seizures on a Novel Locus

ABSTRACT Benign familial infantile seizures (BFIS) is an autosomal dominant epileptic syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures beginning at three to ten months of age. Genetic studies have revealed three susceptibility chromosomal loci on 19q12-q13.1, 16p12-q12 and 2q24. Previously we described the novel locus on 1p36.12-p35.1 for a Chinese family affected with BFIS, and below is a subsequent mutation analysis of candidate genes for the mapped chromosome region. Forty-five genes were selected and subjected to mutation analysis. Thirty-six nucleotide variants were found, none of which led to pathogenic changes, thereby were identified as nucleotide polymorphisms. The analyses suggest those candidate genes that were detected might not be involved in the epileptogenesis of pure BFIS, at least in the Chinese family we studied.