Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort.

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome.

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort.

Genetic factors are important in all forms of dementia, especially in early onset dementia. The frequency of major gene defects in dementia has not been investigated in the Netherlands. Furthermore, whether the recently in a FTD family identified PRKAR1B gene is associated with an Alzheimer's disease (AD) like phenotype, has not been studied. With this study, we aimed to investigate the mutation frequency of the major AD and FTD genes and the PRKAR1B gene in a well-defined Dutch cohort of patients with early onset dementia. Mutation analysis of the genes PSEN1, APP, MAPT, GRN, C9orf72 and PRKAR1B was performed on DNA of 229 patients with the clinical diagnosis AD and 74 patients with the clinical diagnosis FTD below the age of 70 years. PSEN1 and APP mutations were found in, respectively 3.5 and 0.4 % of AD patients, and none in FTD patients. C9orf72 repeat expansions were present in 0.4 % of AD and in 9.9 % of FTD patients, whereas MAPT and GRN mutations both were present in 0.4 % in AD patients, and in 1.4 % resp. 2.7 % in FTD patients. We did not find any pathogenic mutations in the PRKAR1B gene. PSEN1 mutations are the most common genetic cause in Dutch AD patients, whereas MAPT and GRN mutations were found in less than 5 percent. C9orf72 repeat expansions were the most common genetic defect in FTD patients. No pathogenic PRKAR1B mutations were found in the early onset AD and FTD patients of our study.

Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia.

Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.

Supporting the generalist genes hypothesis for intellectual ability/disability: the case of SNAP25.

Intellectual disability (ID) is an unresolved health care problem with a worldwide prevalence rate of 2-3%. For many years, research into the genetic causes of ID and related disorders has mainly focused on chromosomal abnormalities or X-linked genetic deficits. Only a handful of autosomal genes are known to cause ID. At the same time it has been suggested that at least some cases of ID represent an extreme form of normal intellectual ability and therefore that genes important for intellectual ability in the normal range may also play a role in ID. In this study, we tested whether the autosomal SNAP25 gene, which was previously associated with variation in intellectual ability in the normal range, is also associated with ID. The gene product of SNAP25 is an important presynaptic plasma membrane protein, is known to be involved in regulating neurotransmitter release, and has been linked to memory and learning by its effect on long term potentiation in the hippocampus. Allele frequencies of two genetic variants in SNAP25 previously associated with intellectual ability were compared between a group of 636 ID cases (IQ < 70) and a control group of 361 persons of higher than average intellectual ability. We observed a higher frequency of the putative risk allele of rs363050 (P = 0.02; OR = 1.24) in cases as compared to controls. These results are consistent with a role of SNAP25 in ID, and also support the notion that ID reflects the lower extreme of the quantitative distribution of intellectual ability.

The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.

Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6.

DJ-1 was recently identified as a gene product responsible for a subset of familial Parkinson's disease (PD). The mechanisms by which mutations in DJ-1 alter its function and account for PD-related pathology remained largely unknown. We show that DJ-1 is processed by caspase-6 and that the caspase-6-derived C-terminal fragment of DJ-1 fully accounts for associated p53-dependent cell death. In line with the above data, we show that a recently described early-onset PD-associated mutation (D149A) renders DJ-1 resistant to caspase-6 proteolysis and abolishes its protective phenotype. Unlike the D149A mutation, the L166P mutation that prevents DJ-1 dimerization does not impair its proteolysis by caspase-6 although it also abolishes DJ-1 antiapoptotic function. Therefore, we show here that DJ-1 loss of function could be due to impaired caspase-6 proteolysis and we document the fact that various DJ-1 mutations could lead to PD pathology through distinct molecular mechanisms.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Is olfactory impairment in Parkinson disease related to phenotypic or genotypic characteristics?

OBJECTIVE: To evaluate the relation between olfactory impairment (OI) and other impairment domains in Parkinson disease (PD) and the characteristics of OI in patients with certain genotypic characteristics. METHODS: In 295 nondemented patients with PD and 150 controls with a similar overall age and sex distribution, olfactory function was evaluated with the identification (ID) and discrimination (DIS) tests of the Sniffin' Sticks. In patients, demographic and clinical characteristics were evaluated, and genetic analyses were performed. RESULTS: Of all patients, 61% had an impaired ID and 43% had an impaired DIS. No significant correlations >0.4 were found between olfactory scores and other demographic or clinical variables. Age and sex accounted for the 22% explained variance of the ID score regression model, whereas age, sex, and disease duration accounted for the 15% explained variance of the DIS score regression model. Parkin and DJ-1 mutation carriers (homozygous or heterozygous compound, n = 6) had normal ID scores. APOE epsilon2 or APOE epsilon4 carriers had no significantly different olfactory scores than noncarriers. The allele distribution of the alpha-synuclein (SNCA)-REP1 polymorphism in groups with an impaired or normal ID or DIS was comparable. CONCLUSIONS: Olfactory impairment (OI) in Parkinson disease (PD) may be unrelated to other impairment domains of the disease, which may indicate that olfaction is an independent feature of PD. Parkin and DJ-1 mutation carriers had normal identification scores but the number of mutation carriers is too small to draw conclusions. The APOE genotype (APOE epsilon2 or APOE epsilon4 alleles) and SNCA-REP1 polymorphism do not seem to influence olfaction in PD.

Common variants underlying cognitive ability: further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts.

The synaptosomal associated protein of 25 kDa (SNAP-25) gene, located on chromosome 20 p12-12p11.2 encodes a presynaptic terminal protein. SNAP-25 is differentially expressed in the brain, and primarily present in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recently, a family-based genetic association was reported between variation in intelligence quotient (IQ) phenotypes and two intronic variants on the SNAP-25 gene. The present study is a follow-up association study in two Dutch cohorts of 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). It examines the complete genomic region of the SNAP-25 gene to narrow down the location of causative genetic variant underlying the association. Two new variants in intron 1 (rs363043 and rs353016), close to the two previous reported variants (rs363039 and rs363050) showed association with variation in IQ phenotypes across both cohorts. All four single nucleotide polymorphisms were located in intron 1, within a region of about 13.8 kbp, and are known to affect transcription factor-binding sites. Contrary to what is expected in monogenic traits, subtle changes are postulated to influence the phenotypic outcome of complex (common) traits. As a result, functional polymorphisms in (non)coding regulatory sequences may affect spatial and temporal regulation of gene expression underlying normal cognitive variation.

[Parkinson's disease(s): recent insight into genetic factors]. / De ziekte(n) van Parkinson: recente genetische inzichten.

In recent years, 5 genes have been identified that are unambiguously associated with genetic forms of Parkinson's disease. These genes probably explain less than 10% of all cases of Parkinson's disease. Clinically, these genetic forms can closely resemble idiopathic Parkinson's disease. Mutation analysis could be considered in cases involving an age at onset before 45 years, a positive family history or atypical presentations. However, the role of genetic testing in clinical practice remains to be established. Dysfunction of the ubiquitin-proteasome complex, abnormalities of the oxidative stress response and mitochondrial defects represent the three main disease mechanisms implicated in Parkinson's disease caused by these gene mutations. Further research is likely to contribute to the understanding and future treatment of idiopathic Parkinson's disease.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families.

The CHRM2 gene is thought to be involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release and has previously been implicated in higher cognitive processing. In a sample of 667 individuals from 304 families, we genotyped three single-nucleotide polymorphisms (SNPs) in the CHRM2 gene on 7q31-35. From all individuals, standardized intelligence measures were available. Using a test of within-family association, which controls for the possible effects of population stratification, a highly significant association was found between the CHRM2 gene and intelligence. The strongest association was between rs324650 and performance IQ (PIQ), where the T allele was associated with an increase of 4.6 PIQ points. In parallel with a large family-based association, we observed an attenuated - although still significant - population-based association, illustrating that population stratification may decrease our chances of detecting allele-trait associations. Such a mechanism has been predicted earlier, and this article is one of the first to empirically show that family-based association methods are not only needed to guard against false positives, but are also invaluable in guarding against false negatives.