Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic ...variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10
, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10
, β=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10
) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10
) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.
To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases.
Subjects were 2,652 participants of the Erasmus Rucphen Family ...genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls.
We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval CI 0.98-1.70) for MO and 1.70 (95% CI 1.28-2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA.
There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors.
An international study of the epidemiologic characteristics of Creutzfeldt-Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, ...Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland.
Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes.
Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK.
This study has established overall epidemiologic characteristics for Creutzfeldt-Jakob disease (CJD) of all types in a multinational population-based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.
Predicting human phenotypes from genotypes is a newly emerging field with relevance for personalized medicine 1 and forensics 2. However, only a few phenotypic traits can currently be identified from ...DNA information with accuracies sufficient for practical applications 1, most notably human eye (iris) color 3. It could be expected that individual age is too biologically complex to allow a simple and accurate molecular estimation from biological materials. Indeed, previously proposed genetic methods for human age estimation, based on the accumulation of mitochondrial DNA deletions or on telomere shortening, show low accuracies and various technical problems, and are therefore not suitable for practical applications 4. Proposed biochemical methods, such as those based on the accumulation of D-aspartic acid, involve the destructive analysis of specific body parts (such as bones, teeth and ligaments), and suffer from technical issues and bio-degradation 4. In the present study, we demonstrate that human individual age can be estimated accurately and reliably from blood using T-cell DNA rearrangements, and we provide a robust and sensitive real-time quantitative PCR protocol for application in various areas of bioscience.
Aims/hypothesis Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. Methods We assessed body ...composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. Results After accounting for age, sex and inbreeding, heritability ranged from 0.39 for fat mass index to 0.84 for height. We found sex-specific genetic effects for fat percentage (fat%), lean mass, lean mass index (LMI) and fat distribution, but not for BMI and height. Genetic correlations between sexes were significantly different from 1 for fat%, lean mass, LMI, android fat, android:gynoid fat ratio and WHR, indicating that there are sex-specific genes contributing to variation of these traits. Genetic variance was significantly higher in women for the waist, hip and thigh circumference and WHR, implying that genes account for more variance of fat distribution in women than in men. Environmental variance was significantly higher in men for the android:gynoid fat ratio. Conclusions/interpretation Sex-specific genetic effects underlie sexual dimorphism in several body composition traits. The findings are relevant for studies on the relationship of body composition with common diseases like cardiovascular disease and type 2 diabetes and for genetic association studies.
Core Ideas
We provide detailed analysis of various forms of the dynamic capillarity coefficient.
We focus on the region of saturation overshoot at larger saturation.
The results are evaluated with ...the aid of experimental observations.
Gravity‐driven fingering has been observed during downward infiltration of water into dry sand. Moreover, the water saturation profile within each finger is non‐monotonic, with a saturation overshoot at the finger tip. As reported in the literature, these effects can be simulated by an extended form of the Richards equation, where a dynamic capillarity term is included. The coefficient of proportionality is called the dynamic capillarity coefficient. The dynamic capillarity coefficient may depend on saturation. However, there is no consensus on the form of this dependence. We provide a detailed traveling wave analysis of four distinctly different functional forms of the dynamic capillarity coefficient. In some forms, the coefficient increases with increasing saturation, and in some forms, it decreases. For each form, we have found an explicit expression for the maximum value of saturation in the overshoot region. In current formulations of dynamic capillarity, if the value of the capillarity coefficient is large, the value of saturation in the overshoot region may exceed unity, which is obviously nonphysical. So, we have been able to ensure boundedness of saturation regardless of the value of the dynamic capillarity coefficient by extending the capillary pressure–saturation relationship. Finally, we provide a qualitative comparison of the results of traveling wave analysis with experimental observations.
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 ⩾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.
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The First Key Symposium was held in Stockholm, Sweden, 2–5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive ...Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.
In this paper, we consider Mandel's problem in the context of nonlinear single-phase poroelasticity, where it is assumed that the fluid is sightly compressible and porosity and permeability are given ...functions of the volume strain. In the first part of the paper we prove well-posedness of the time-discrete incremental problem by recasting the equations in an abstract form involving a pseudo-monotone operator. Further, we show existence of a Lyapunov functional yielding a global time discrete solution. In the second part, we investigate numerically the behavior of the poroelastic structure. In particular, we verify the assumptions leading to Mandel's solution. We also demonstrate some consequences of the proposed nonlinearities.
Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but ...with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt–Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease to include findings from magnetic resonance imaging scans.
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