Marieke C.J. Dekker

PARK7, a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, on Chromosome 1p36

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism.

Iron overload increases oxidative stress and may lead to neurodegenerative disease like Parkinsons disease (PD). We studied the role of mutations in the hemochromatosis gene HFE in PD and other parkinsonism (non-PD PS) in two population-based series. The first series consisted of 137 patients with PD and 47 with non-PD PS, and the second of 60 patients with PD and 25 with non-PD PS. In the first series, PD patients were significantly more often homozygous for the C282Y mutation than controls (P=0.03). Patients with non-PD PS in both series were more often carriers for the C282Y mutation than controls (P=0.009, P=0.006, respectively). Our data are hampered by small numbers, yet suggest that the C282Y mutation increases the risk of PD and non-PD PS. The rarity of this genotype requires a large series of patients to prove our hypothesis.

Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach

BACKGROUND Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisol(AUC)), (2) performed a genome wide association study (GWAS) of cortisol(AUC), and (3) tested the association of identified cortisol-related SNPs with depressive symptoms. METHODS We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n=1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n=2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n=2836) to replicate the GWAS findings. RESULTS Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisol(AUC) (p<1×10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1×10(-06) (rs8062512, rs2252459), but these associations could not be replicated. CONCLUSIONS These results suggest that variation in the FKBP5 gene is associated with both cortisol(AUC) and the likelihood of depressive symptoms.

Clinical features and neuroimaging of PARK7-linked parkinsonism

We recently reported linkage to chromosome 1p36 (the PARK7‐locus) in a family with early‐onset parkinsonism. Linkage to this locus has since been confirmed in an independent data set. We describe clinical and neuroimaging features of the 4 patients in the original PARK7‐linked kindred. Age at onset of parkinsonism varied from 27 to 40 years. Clinical progression was slow, and response to dopaminergic therapy good. The clinical spectrum ranged from mild hypokinesia and rigidity, to severe parkinsonism with levodopa‐induced dyskinesias and motor fluctuation. Three of four patients with PARK7‐linked parkinsonism exhibited psychiatric disturbances. Structural neuroimaging was unremarkable, but functional imaging of the brain, carried out in 3 patients, showed significant evidence for a presynaptic dopamine deficit, and assessment of cerebral glucose metabolism, as carried out in 1 patient, showed possible cerebellar involvement.

Attention-deficit/hyperactivity disorder (ADHD): parents' judgment about school, teachers' judgment about home.

Abstract.Objective:The aim of this study was to separate sources of observer and situational variance in reporting attentiondeficit/hyperactivity disorder (ADHD) symptomatology.Method:In a sample of 30 children diagnosed with ADHD, ADHD symptomatology was assessed with the Diagnostic Interview Schedule for Children–Parent Version (DISC-P), with parents and teachers as informants. Both parents and teachers reported about the child’s ADHD symptomatology at home as well as at school.Results:Parents and teachers showed high within-observer cross-situational presence of ADHD symptoms. However, the between-observer agreement on the presence of ADHD symptoms within the same situation (home or school) was low. This pattern held equally true for attention/concentration and hyperactivity/impulsivity symptom scores.Conclusions:In evaluating ADHD symptomatology, it is important to obtain independent reports about the child’s behaviour at school from the teacher and about the child’s behaviour at home from the parents.

PET neuroimaging and mutations in the DJ-1 gene

Summary.Mutations in the DJ-1 gene lead to autosomal recessive early-onset parkinsonism. We performed F-DOPA and FDG PET neuroimaging in two parkinsonism patients homozygous for DJ-1 mutations, three relatives heterozygous for a DJ-1 mutation and one non-carrier, all from the originally described kindred from The Netherlands. Their characteristics were compared to those of typical Parkinson’s disease patients and healthy controls. Both parkinsonism patients had reduced F-DOPA uptake concordant with typical Parkinson’s disease. In the, clinically unaffected, heterozygous relatives, F-DOPA metabolism was unremarkable, thus not suggesting a dosage effect of the DJ-1 gene.

Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7.

Abstract. Autosomal recessive, early onset parkinsonism (AREP) is genetically heterogeneous. Mutations in the parkin gene (PARK2 locus, chromosome 6q) account for up to 50% of AREP families. The parkin protein displays ubiquitin-ligase activity for different targets, which accumulate in the brain of patients with parkin defect and might cause neurodegeneration. Two new AREP loci (PARK6 and PARK7) have been recently mapped on chromosome 1p and confirmed in independent datasets, suggesting that both might be frequent. The three AREP forms display similar clinical phenotypes. Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci. This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinsons disease.

The CIRCORT database: Reference ranges and seasonal changes in diurnal salivary cortisol derived from a meta-dataset comprised of 15 field studies

Diurnal salivary cortisol profiles are valuable indicators of adrenocortical functioning in epidemiological research and clinical practice. However, normative reference values derived from a large number of participants and across a wide age range are still missing. To fill this gap, data were compiled from 15 independently conducted field studies with a total of 104,623 salivary cortisol samples obtained from 18,698 unselected individuals (mean age: 48.3 years, age range: 0.5-98.5 years, 39% females). Besides providing a descriptive analysis of the complete dataset, we also performed mixed-effects growth curve modeling of diurnal salivary cortisol (i.e., 1-16h after awakening). Cortisol decreased significantly across the day and was influenced by both, age and sex. Intriguingly, we also found a pronounced impact of sampling season with elevated diurnal cortisol in spring and decreased levels in autumn. However, the majority of variance was accounted for by between-participant and between-study variance components. Based on these analyses, reference ranges (LC/MS-MS calibrated) for cortisol concentrations in saliva were derived for different times across the day, with more specific reference ranges generated for males and females in different age categories. This integrative summary provides important reference values on salivary cortisol to aid basic scientists and clinicians in interpreting deviations from the normal diurnal cycle.

Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in the Human Hypothalamus

The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic‐pituitary‐adrenal (HPA) axis setpoint regulation. The enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting biologically inactive cortisone to its active form cortisol. The present study aimed to assess 11βHSD1 expression in the human hypothalamus. We studied 11βHSD1 expression in five frozen and four formalin‐fixed, paraffin‐embedded human hypothalami (obtained from the Netherlands Brain Bank) by the polymerase chain reaction and immunocytochemistry, respectively. 11βHSD1 mRNA was expressed in the area of the suprachiasmatic nucleus, which is the biological clock of the brain, in the supraoptic nucleus and paraventricular nucleus (PVN), and in the infundibular nucleus, which is the human homologue of the rodent arcuate nucleus. 11βHSD1 was detected by immunocytochemistry in the same nuclei. In the PVN, neuronal 11βHSD1 immunoreactivity colocalised with corticotrophin‐releasing hormone (CRH), arginine vasopressin and oxytocin, as shown by dual fluorescence staining. Our data demonstrate that 11βHSD1 is widely expressed in the human hypothalamus. Its colocalisation with CRH in the PVN suggests a role in modulation of glucocorticoid feedback of the HPA axis, whereas the expression of 11βHSD1 in additional and functionally diverse hypothalamic nuclei points to a role for the enzyme in the regulation of metabolism, appetite and circadian rhythms.

Prospects of genetic epidemiology in the 21st century

Genetic epidemiology is a young but rapidly developing discipline. Although its early years were largely dedicated to family-based research in monogenic disorders, now genetic–epidemiologic research increasingly focuses on complex, multifactorial disorders. Along with the development of the human-genome map and advances in molecular technology grows the importance of genetic–epidemiologic applications. Large-scale population-based studies, requiring close integration of genetic and epidemiologic research, determine future research in the field. In this paper, we review the basic principles underlying genetic–epidemiologic research, such as molecular genetics and familial aggregation of disease, as well as the typical study approaches of genome screening and candidate-gene studies.