Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache.

Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

Genetic Screening of Plasticity Regulating Nogo-Type Signaling Genes in Migraine.

Migraine is the sixth most prevalent disease in the world and a substantial number of experiments have been conducted to analyze potential differences between the migraine brain and the healthy brain. Results from these investigations point to the possibility that development and aggravation of migraine may include grey matter plasticity. Nogo-type signaling is a potent plasticity regulating system in the CNS and consists of ligands, receptors, co-receptors and modulators with a dynamic age- and activity-related expression in cortical and subcortical regions. Here we investigated a potential link between migraine and five key Nogo-type signaling genes: RTN4, OMGP, MAG, RTN4R and LINGO1, by screening 15 single nucleotide polymorphisms (SNPs) within these genes. In a large Swedish migraine cohort (749 migraine patients and 4032 controls), using a logistic regression with sex as covariate, we found that there was no such association. In addition, a haplotype analysis was performed which revealed three haplotype blocks. These blocks had no significant association with migraine. However, to robustly conclude that Nogo-type genotypes signaling do not influence the prevalence of migraine, further studies are encouraged.

S100B polymorphisms are associated with age of onset of Parkinson's disease.

BACKGROUND: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. METHODS: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. RESULTS: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. CONCLUSIONS: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.

The choroid plexus harbors a circadian oscillator modulated by estrogens.

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian oscillator in mammals. However, extra-SCN structures in the brain also display daily rhythms. Recently, we have demonstrated that the choroid plexus (CP) expresses core clock genes that are subjected to circadian regulation in a sex-dependent manner. By using CP explants cultured from female knock-in mice carrying the Period-luciferase transgene, we show that CP exhibits endogenous circadian rhythms of PERIOD2::LUCIFERASE expression. Furthermore, we demonstrate that estrogen declines following ovariectomy modulates the daily rhythm expression of Bmal1, Per1 and Per2 in female rat CP, corroborating data obtained in experiments where rat CP epithelial cell (CPEC) cultures were incubated with 17ß-estradiol (E2). The molecular mechanism underlying these effects was also investigated, and we provide evidence that the estrogen receptor (ER) mediates the response of clock genes to E2. In conclusion, our study proves that the CP harbors a circadian oscillator that is modulated by estrogens and demonstrates that E2 regulation occurs through an estrogen-receptor-dependent mechanism.

Screening of Two ADH4 Variations in a Swedish Cluster Headache Case-Control Material.

BACKGROUND: Cluster headache (CH) is a severe neurovascular disorder and an increasing amount of evidence points to a genetic contribution to this disease. When CH was first described, it was observed that alcohol may precipitate an attack during the active phase of the disease. The alcohol dehydrogenase 4 (ADH4) gene encodes an enzyme which contributes to the metabolization of alcohol and is, therefore, an interesting candidate gene for CH. Two Italian groups have reported association of the single nucleotide polymorphism (SNP) rs1126671 located in the ADH4 gene with an increased risk of CH in Italy. In addition, one of the groups found an association between the ADH4 SNP rs1800759 and CH. OBJECTIVE: To perform a replication study on the ADH4 SNPs rs1126671 and rs1800759 in a large homogeneous Swedish case-control cohort in order to further investigate the possible contribution of ADH4 to CH. METHODS: A total of 390 unrelated patients diagnosed with CH and 389 controls representing a general Swedish population were recruited to the study. DNA samples from patients and controls were genotyped for the two ADH4 SNPs rs1126671 and rs1800759 using quantitative real-time polymerase chain reaction. Statistical analyses of genotype, allele and haplotype frequencies for the two SNPs were performed and compared between patients and controls. RESULTS: For rs1126671, the minor allele frequency (A allele) was 32.8% (n = 254) in controls compared with 31.9% (n = 249) in CH patients. The minor allele frequency (A allele) of rs1800759 was 42.3% (n = 324) in controls and 41.9% (n = 327) in CH patients. Statistical analysis showed no significant differences in allele as well as in genotype or haplotype frequencies between the patient and control group for either SNP. This was also seen after stratifying the patient group for experiencing alcohol as a trigger factor. CONCLUSIONS: The data did not support an association of the ADH4 SNPs rs1126671 and rs1800759 with CH. A comparison with previous studies revealed variance in genotype, allele, and haplotype frequencies among the different populations which might contribute to the contradictory results. Although a significant association with CH in Swedish case-control group was not found, ADH4 as a candidate gene for CH could not be excluded.

PITX3 polymorphism is associated with early onset Parkinson's disease.

PITX3 is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons, the gene of which is disrupted in a putative mouse model for Parkinson's disease (PD). The A-allele of a HapMap tagging SNP (rs4919621) that was genotyped in a population of 361 PD patients, 69 of which had early onset, and in 333 controls, was significantly more common in PD patients with an early age of onset when compared either to controls (p=0.002) or to PD patients with late onset (p=0.001). In contrast, a previous finding suggesting a SNP (rs3758549) in the putative promoter region of the PITX3 gene to be associated with PD could not be replicated.

S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson's disease in Sweden.

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that removes ubiquitin from the C-terminal end of substrates and a component of the ubiquitin-proteasome system. A protective effect of a UCH-L1 variant, S18Y, was suggested since the common variant was found to be inversely associated with sporadic Parkinson's disease (PD). We investigated the association of S18Y in our Swedish PD material. The tyrosine variant was significantly inversely associated with PD (P=0.049) and with a low age of onset (50 years) (P=0.017) in the case-control material, supporting the hypothesis of a protective function.

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish Parkinson cohort and a healthy nonagenarian.

Specific variants of Leucine-rich repeat kinase 2 (LRRK2) have been shown to associate with Parkinson's disease (PD). Several mutations have been found in PD populations from different parts of the world. We investigated the occurrence of three mutations (R1441G/C/H, G2019S, and I2020T) in our Swedish case-control material and identified four carriers of the G2019S mutation in 284 PD cases and 1 95-year-old carrier in 305 controls. The other two variants were absent in our material. We conclude that the LRRK2 G2019S mutation constitutes a significant factor for PD in the Swedish population and that it is not completely penetrant.