MAPT IVS1+124 C>G modifies risk of LRRK2 G2385R for Parkinson's disease in Chinese individuals

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08–3.19; p = 0.014), whereas MAPT IVS1+124 C>G was not (p = 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14–4.54; p = 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals.     

Clusterin variants are not associated with southern Chinese patients with Alzheimer's disease

Recent genome-wide association studies identified clusterin (CLU) to be associated with sporadic Alzheimer's disease. To help clarify the relevance of CLU as genetic determinant of AD, we analyzed its association in southern Chinese Han population. This study comprised 499 sporadic Alzheimer's disease patients and 592 unrelated age- and sex-matched healthy controls. Four single-nucleotide polymorphisms (rs2279590, rs9331888, rs11136000, and rs1532278) within CLU were selected for genotyping. No positive association was found between the CLU variants and AD. Our study suggests that CLU variants may not be an AD susceptibility factor in southern Chinese Han population.     

Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer's disease from mainland China

Recently, 3 rare coding variants significantly associated with Alzheimer's disease (AD) risk have been identified in western populations using whole exome sequencing method, including p.R47H in TREM2, p.V232M in PLD3, and p.T835M in UNC5C. To examine whether these variants are genetic risk factors in patients with AD from mainland China, we sequenced exon 2 of TREM2, exon 9 of PLD3, and exon 15 of UNC5C in Chinese Han population including 360 patients with AD and 400 control individuals. As a result, none of these 3 variants were identified in all subjects, however, 1 novel variant (p.A130V) in TREM2 and 4 novel variants (p.Q860H, p.T837K, p.S843G, and p.V836V) in UNC5C were detected in unrelated patients with late-onset AD. These findings suggest the 3 rare coding variants might not play an important role in AD risk in mainland China.     

Low frequency of common LRRK2 mutations in Mexican patients with Parkinson's disease

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5–6% of familial Parkinson's disease (PD) and 1–2% of sporadic PD. These mutations represent the most frequent cause of autosomal dominant PD, particularly in certain ethnic groups. In this first report concerning LRRK2 mutations in Mexican-mestizos, we screened 319 consecutive PD patients (186 males; 133 females; mean age at onset: 52.4 years) for LRRK2 mutations in exons 31 and 41 and for the mutation in exon 35, which produces the Y1699C substitution. Three (0.94%) patients, two with sporadic PD and one with familial PD (disease mean age at onset, 53.3 years), were heterozygous for LRRK2 mutations. Of these three, two patients had one of two different mutations in exon 31 (R1441G and R1441H, respectively); the other patient carried the G2019S mutation in exon 41. The Y1699C mutation was absent from this PD sample. Four additional subjects, unaffected relatives of one PD patient with a mutation in LRRK2, were subsequently genetically tested. None of the three LRRK2 mutations identified was present in 200 neurologically healthy Mexican control individuals. These findings have important implications for molecular testing of LRRK2 mutations in Mexican PD patients.     

Novel GIGYF2 gene variants in patients with Parkinson's disease in Chinese population

The Grb10-Interacting GYF Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, has been reported as a PARK11 gene with a causal role in familial Parkinson's disease (PD) in Italian and French populations. However, there is no comprehensive study of GIGYF2 gene conducted in Chinese patients with PD from mainland China. The 27 coding exons and intron/exon boundaries of the GIGYF2 gene were sequenced in 300 sporadic patients with Parkinson's disease. Eight heterozygous and one homozygous novel missense variants were identified in nine patients with PD, and not in 300 controls. p.Leu580Phe locates in the GYF domain and might interrupt the potentially function of GIGYF2 protein. Another variant Gln979stop encodes a truncated protein. In conclusion, we identified nine novel variants in GIGYF2 gene, which might be associated with PD in the Chinese population.     

Mutational analysis of FBXO7 gene in Parkinson's disease in a Taiwanese population

Mutations in the FBXO7 gene cause an autosomal-recessive early-onset parkinsonism with pyramidal tract signs. Its role in typical Parkinson's disease (PD) without pyramidal features is unclear. We assayed FBXO7 gene in 900 participants comprising 448 PD patients and 452 age- and sex-matched control subjects from Taiwan. The entire FBXO7 coding region and intron-exon boundaries were sequenced. We identified 2 novel missense substitutions, p.Ile87Thr and p.Asp328Arg, in a single heterozygous state in 2 early-onset PD patients individually (1.1% early-onset PD). These 2 variants were not observed in control subjects with a total of 904 normal alleles. Additionally, we also found 1 noncoding variant, exon 1 IVS-329C>T, modestly associated with PD. The frequency of the CT/TT genotype was higher in PD patients compared with control subjects (odds ratio, 1.43; 95% confidence interval, 1.02–2.01; p = 0.04). The clinical phenotypes of genetic variant carriers are similar to that seen in idiopathic PD. We conclude that FBXO7 gene contributes little to typical PD in our population. Further studies in other ethnic cohorts will be important to address its potential pathophysiological role in PD.     

Alzheimer's disease and Parkinson's disease genome-wide association study top hits and risk of Parkinson's disease in Korean population

Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping clinical and pathological features, suggesting a common pathway for these 2 neurodegenerative disorders. Here we investigated the association of both AD and PD GWAS top hits with PD susceptibility. We selected 25 single nucleotide polymorphisms (SNPs) in 9 genes (ABCA7, APOE, BST1, CLU, CR1, LRRK2, PARK16, PICALM, and SNCA) that were genotyped in 1036 PD case patients and 1208 controls. Case patients and controls were all ethnic Koreans. Logistic regression analysis was performed to calculate age- and sex-adjusted odds ratios. None of the AD-susceptibility loci (ABCA7, APOE, CLU, CR1, and PICALM) showed statistically significant association with PD susceptibility. In contrast, we replicated associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility in Koreans. Of those, the SNCA SNP rs11931074 showed the most significant association with PD susceptibility (adjusted odds ratio = 1.48; 95% confidence interval = 1.31–1.67; p = 2.20E-10). In a logistic regression analysis with SNPs coded under an additive model, there was no significant genetic interaction between the LRRK2 and the PARK16 locus gene RAB7L1 in PD risk. Our results confirm the associations of SNCA, LRRK2, BST1, and PARK16 with PD susceptibility and fail to show significant associations of AD genome-wide association study (GWAS) top hits with PD susceptibility in a Korean population.     

Genetic analysis of LRRK2 A419V variant in ethnic Chinese

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common causes of autosomal dominant and sporadic forms of Parkinson's disease (PD). The A419V variant has been suggested to be a potential risk variant but its role among Chinese is unclear. We genotyped LRRK2 A419V variant to investigate the association with risk of PD. A total of 1314 subjects comprising 729 patients with PD and 585 controls were genotyped. Twenty-two (3.0%) patients were heterozygous carriers for the A419V variant, and the frequency was higher compared with controls (0.7%, p = 0.003). The association was seen among the younger age group (early onset PD patients vs. controls: p = 0.0005), but was not significant among the older age group (late onset PD patients vs. controls: p = 0.17). We showed a significant association of LRRK2 A419V variant among early onset PD in the ethnic Han Chinese population but not among late onset PD. Further replication studies in additional Chinese and other Asian cohorts will be important to address its potential pathophysiologic role.     

A novel LRRK2 mutation in a mainland Chinese patient with familial Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are known to cause typical, late-onset familial Parkinson's disease in different geographic origins. However, there was no report about mutations of LRRK2 gene in mainland China. The 51 coding exons and intron/exon boundaries of the LRRK2 gene were sequenced in nine families with Parkinson's disease. A novel LRRK2 missense mutation resulting in a single amino acid substitution K616R was present in one family with a dominant form of PD, and not in 200 controls. The patient presented with slowly progressive resting tremor, dyskinesia, and responded well to l-dopa. In conclusion, we identified a novel mutation in LRRK2 gene, which was the first mutation of LRRK2 found in the mainland Chinese population with familial Parkinson's disease.     

Genetic analysis of LRRK2 P755L variant in Caucasian patients with Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified both in familial and sporadic cases of PD. Recently, a P755L variant in the LRRK2 gene has been found to be responsible for 2% of Chinese patients with sporadic PD. To evaluate the frequency of the LRRK2 P755L variant in North American Caucasian patients with PD, we screened 426 PD patients and 37 additional patients with the combination of PD and essential tremor (ET) from our Parkinson Disease Center and Movement Clinic at Baylor College of Medicine. No P755L variant was found in our PD cohort. Therefore, we conclude that LRKK2 P755L variant is a rare cause of Caucasian PD and has no diagnostic utility in genetic testing of this population of patients.     

Triggering receptor expressed on myeloid cells 2 variants are rare in Parkinson's disease in a Han Chinese cohort

Recent studies have reported that a rare nonsynonymous variant rs75932628-T in the TREM2 gene is associated with increased risk of Alzheimer's disease and Parkinson's disease (PD) in European-descended populations. However, the association between rare TREM2 mutations and PD risk remains unknown in Chinese population. We directly sequenced exon2 of TREM2 in a cohort of 476 PD patients and 432 healthy controls from a Han Chinese population. Rs75932628-T (p.R47H) was found in 0.2% of PD cases (1/476) but in none of the controls (0/432, p = 1.000), with a minor allele frequency of 0.06% among the 908 subjects. Our findings suggest that variants in exon2 of TREM2 are extremely rare, and it is not a genetic risk factor for PD in the southern Han Chinese population.     

Genetic variation in PICALM and Alzheimer's disease risk in Han Chinese

The current study was conducted to investigate the association of phosphatidylinositol-binding clathrin assembly protein gene (PICALM) with late-onset Alzheimer's disease (LOAD) risk in Han Chinese. We first sequenced PICALM for variants in a small sample (n = 100), and the selected variants were then genotyped in a larger cohort (n = 2292). Sequencing analysis identified 16 variants within PICALM including 5 new variants with extreme low frequency in the northern Han Chinese population. However, in the subsequent genotyping, none showed a significant association with LOAD risk after Bonferroni correction. These findings implicate that PICALM might not play a major role in the genetic predisposition to LOAD in Han Chinese.     

Lack of association between CALHM1 p.P86L variation and Alzheimer's disease in the Han Chinese population

In recent years, several studies have reported calcium homeostasis modulator 1 (CALHM1) was a potential gene related to Alzheimer's disease (AD) susceptibility. However, whether CALHM1 p.P86L variation (rs2986017), a risk factor for AD is still controversial. Two independent studies have been performed in the Chinese population and the conclusions have not reached an agreement. In the present study, we performed a replication case–control study in 1301 Chinese subjects including 452 sporadic AD patients and 849 unrelated age and gender-matched controls, to determine whether this variation is a risk factor for AD in the Han Chinese population. We failed to replicate the positive association between the CALHM1 p.P86L variation and AD. In addition, we also examined p.P86L variation in a meta-analysis of 5 independent studies performed in Chinese and other Asian populations and negative association was found in total 2328 AD patients and 2865 controls. Our study suggests that CALHM1 p.P86L variation may not be an AD susceptibility factor in the Han Chinese population.     

Exome array study did not identify novel variants in Alzheimer's disease

Genetic variants so far identified explain a small fraction of the overall inherited risk of Alzheimer's disease (AD). We aimed to identify novel genetic variants in AD using exome array that contains comprehensive panel. We genotyped 295,988 variants in 1005 subjects (400 AD cases and 605 controls) using Axiom Exome Genotyping Array that contains a pool of variants discovered in over 16 major human exome sequencing initiatives. Logistic regression analysis and the sequence kernel association optimal test were performed. The APOE, APOC1, and TOMM40 showed significant associations with AD in the single variant analysis. However, no significant association of other variants with AD was observed. This exome array study failed to identify novel genetic variants in AD.     

Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium

Background

We and others recently identified the gene underlying PARK8 linked Parkinson''s disease (PD). This gene, LRRK2, contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease.

Methods

We undertook a case‐control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel.

Results

We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter‐population variability in the strength of LD across this locus.

Conclusions

To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD.     

Influence of Alzheimer's disease genes on cognitive decline: the Guangzhou Biobank Cohort Study

Cognitive decline is a reduction in cognitive ability usually associated with aging, and those with more extreme cognitive decline either have or are at risk of progressing to mild cognitive impairment and dementia including Alzheimer's disease (AD). We hypothesized that genetic variants predisposing to AD should be predictive of cognitive decline in elderly individuals. We selected 1325 subjects with extreme cognitive decline and 1083 well-matched control subjects from the Guangzhou Biobank Cohort Study in which more than 30,000 southern Chinese older people have been recruited and followed up. Thirty single-nucleotide polymorphisms in 29 AD-associated genes were genotyped. No statistically significant allelic associations with cognitive decline were found by individual variant analysis. At the level of genotypic association, we confirmed that the APOE ε4 homozygote significantly accelerated cognitive decline and found that carriers of the ACE rs1800764_C allele were more likely to show cognitive decline than noncarriers, particularly in those without college education. However, these effects do not survive after multiple testing corrections, and together they only explain 1.7% of the phenotypic variance in cognitive score change. This study suggests that AD risk variants and/or genes are not powerful predictors of cognitive decline in our Chinese sample.     

LRRK2 p.G2019S Mutation Is Not Common among Alzheimer’s Disease Patients in Brazil

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson’s Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer’s Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.     

Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention

Recent studies have found an association between a variant in triggering receptor expressed on myeloid cells 2 (TREM2) (rs75932628-T) and both Alzheimer's disease (AD) and cognitive function in individuals aged 80–100 years. The role of TREM2 in younger, asymptomatic individuals is unknown. We examined this variant in 1148 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Thirteen individuals carried the T risk allele. Carriers were more likely to have a parental history of AD (100% of carriers vs. 70% of noncarriers; p = 0.01) and, among the parental history subset, families with a TREM2 carrier had a younger maternal age of AD onset than noncarriers (67.9 vs. 75.6 years; p = 0.03). There was no significant association between TREM2 carrier status and cognitive function or decline. In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.     

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid β (Aβ) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.     

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ² = 6.446, p = 0.040 for genotypic distribution; χ² = 5.762, p = 0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.