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Paragangliomas of the head and neck are slow growing tumors which rarely show malignant progression. Familial transmission has been described consistent with an autosomal dominant mode of inheritance. Clinical manifestations of hereditary... more
Paragangliomas of the head and neck are slow growing tumors which rarely show malignant progression. Familial transmission has been described consistent with an autosomal dominant mode of inheritance. Clinical manifestations of hereditary paragangliomas are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female until subsequent transmittance of the gene through a male carrier. This finding strongly suggests that genomic imprinting is involved. We report the results of a linkage study on a large Dutch pedigree with hereditary paragangliomas. Highly significant evidence for genetic linkage to chromosome 11q23-qter with the anonymous DNA marker D11S147 was detected with a peak lod score of 6.0 at a recombination fraction theta = 0.0. Likelihood calculations yielded an odds ratio of 2.7 x 10(6) in favor of genomic imprinting versus the absence of genomic imprinting.
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Research Interests: Genetics, Human Genetics, Population Genetics, Molecular Genetics, Simulation, and 16 moreCytogenetics, Genetics of complex disease, Population, Humans, Female, Clinical Genetics, Male, Linkage, Netherlands, Linkage Disequilibrium, European Continental Ancestry Group, Short Tandem Repeat, In Silico, Genetic distance, Genetic Markers, and Genetic Isolation
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The struggle to identify susceptibility genes for complex disorders has stimulated geneticists to develop new approaches. One approach that has gained considerable interest is to focus on genetically isolated populations rather than on... more
The struggle to identify susceptibility genes for complex disorders has stimulated geneticists to develop new approaches. One approach that has gained considerable interest is to focus on genetically isolated populations rather than on the general population. There remains much controversy and theoretical debate over the feasibility and advantages of such populations, but recent results speak in favor of the feasibility
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Variation in human behavior may be caused by differences in genotype and by non-genetic differences ("environment") between individuals. The relative contributions of genotype (G) and environment (E) to phenotypic variation can... more
Variation in human behavior may be caused by differences in genotype and by non-genetic differences ("environment") between individuals. The relative contributions of genotype (G) and environment (E) to phenotypic variation can be assessed with the classical twin design. We illustrate this approach with longitudinal data collected in 5 and 12-year-old Dutch twins. At age 5 data on cognitive abilities as assessed with a standard intelligence test (IQ), working memory, selective and sustained attention, and attention problems were collected in 237 twin pairs. Seven years later, 172 twin pairs participated again when they were 12 years old and underwent a similar protocol. Results showed that variation in all phenotypes was influenced by genetic factors. For IQ the heritability estimates increased from 30% at age 5, to 80% at age 12. For executive functioning performance genetic factors accounted for around 50% of the variance at both ages. Attention problems showed high heri...
Research Interests: Genetics, Sustained Attention, Intelligence, Cognitive development, Cognition, and 23 moreAging, Working Memory, Executive Function, Thinking, Humans, Child, Human behavior, Female, Male, Developmental disabilities, Netherlands, Phenotype, Clinical Sciences, Longitudinal Studies, Genotype, Cognitive Ability, Longitudinal data, Twin Study, Intelligence tests, Environment, Neurosciences, Predictive value of tests, and Inheritance Patterns
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Research Interests:
Small-vessel diseases of the brain underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. In this report, we show that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha1,... more
Small-vessel diseases of the brain underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. In this report, we show that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha1, predisposes both newborn and adult mice to intracerebral hemorrhage. Surgical delivery of mutant mice alleviated birth-associated trauma and hemorrhage. We identified a
Research Interests: Microcirculation, England, Stroke, Brain, Humans, and 20 moreMutation, Mice, Female, Animals, Male, Ischemic Stroke, Pedigree, Risk factors, Spectrum, Intracerebral Hemorrhage, Environmental Stress, Risk Factors, Physiological Stress Markers, Cerebral small vessel disease, Renal Artery, Glomerular Basement Membrane, Collagen Type IV, Cerebrovascular Accident, Cerebral Hemorrhage, and New England Journalof Medicine
Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of... more
Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental dis- order characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid
Research Interests: Genetics, Human Evolution, Molecular Biology, Intelligence, Molecular Evolution, and 20 moreFamily, Adolescent, Biological Sciences, Association study, Brain, Humans, Child, Microcephaly, Female, Human Cognition, Male, Human Molecular Genetics, Biological evolution, Human Brain, Genotype, Adult, Adaptive evolution, Cognitive Ability, Large Scale, and Experimental Validation
The mouse and human brain express a large number of noncoding RNAs (ncRNAs). Some of these are known to participate in neural progenitor cell fate determination, cell differentiation, neuronal and synaptic plasticity and transposable... more
The mouse and human brain express a large number of noncoding RNAs (ncRNAs). Some of these are known to participate in neural progenitor cell fate determination, cell differentiation, neuronal and synaptic plasticity and transposable elements derived ncRNAs contribute to somatic variation. Dysregulation of specific long ncRNAs (lncRNAs) has been shown in neuro-developmental and neuro-degenerative diseases thus highlighting the importance of lncRNAs in brain function. Even though it is known that lncRNAs are expressed in cells at low levels in a tissue-specific manner, bioinformatics analyses of brain-specific ncRNAs has not been performed. We analyzed previously published custom microarray ncRNA expression data generated from twelve human tissues to identify tissue-specific ncRNAs. We find that among the 12 tissues studied, brain has the largest number of ncRNAs. Our analyses show that genes in the vicinity of brain-specific ncRNAs are significantly up regulated in the brain. Investigations of repeat representation show that brain-specific ncRNAs are significantly more likely to originate in repeat regions especially DNA/TcMar-Tigger compared with non-tissue-specific ncRNAs. We find SINE/Alus depleted from brain-specific dataset when compared with non-tissue-specific ncRNAs. Our data provide a bioinformatics comparison between brain-specific and non tissue-specific ncRNAs. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.
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Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed... more
Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.
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Research Interests: Risk, Adolescent, Brain, Humans, Child, and 12 moreMutation, Europe, United States, Female, Male, Young Adult, Pedigree, Aged, Middle Aged, Adult, Genetic variation, and Parkinson Disease
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant... more
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio…
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Research Interests: Humans, Female, Male, Clinical Sciences, Aged, and 5 moreMiddle Aged, Genotype, Adult, Frontotemporal Dementia, and Neurosciences
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Research Interests: Cognitive Science, Adolescent, Family history, Movement disorders, Humans, and 21 moreProtein Kinases, Genetic Testing, Movement, Female, Male, Polymerase Chain Reaction, Mutation Detection, Genetic Screening, Cost effectiveness, Phenotype, Clinical Sciences, Aged, Middle Aged, Genotype, Adult, Cost Benefit Analysis, Disease Progression, Indexation, Autosomal Recessive, Age of Onset, and Parkinson Disease
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The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic... more
The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits is to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting G6G interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidate interactions that can be empirically tested. In both the mouse and human data we observed two-locus genet...
Research Interests: Computational Biology, Population Genetics, Multidisciplinary, Methods, Humans, and 14 moreMice, Animals, Feasibility Studies, Genome, Gene Regulatory Networks, PLoS one, Human Genome, Genetic Differentiation, Potential Function, Genetic Divergence, Phenotypic variation, Interaction effect, Complex Traits, and Individual Difference
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Research Interests: Genetics, Population Genetics, Quantitative Genetics, Multidisciplinary, Mice, and 16 moreHaplotypes, Maximum Likelihood, Animals, Complex network, Genetic Map, EM algorithm, PLoS one, Molecular cloning, Genotype, Single Nucleotide Polymorphism, Molecular Marker, Linkage Disequilibrium, Quantitative Trait Loci, High Density Concrete, Statistical Model, and Nucleotides
Research Interests: Genetics, Multiple System Atrophy, Natural History, Genome Wide Association Studies (GWAS), Multidisciplinary, and 14 moreQuality Control, Alpha Synuclein, Multiple testing, Humans, Female, Male, Cerebellar ataxia, PLoS one, Aged, Middle Aged, Genotype, Genetic variation, Genetic Association, and Case Control Studies
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Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding... more
Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.