Medical Research Council Human Genetics Unit

Edinburgh, United Kingdom

Medical Research Council Human Genetics Unit

Edinburgh, United Kingdom

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PubMed | Center for Clinical Epidemiology and Biostatistics, Max Planck Institute for Intelligent Systems (Tübingen), Hunter Medical Research Institute, Universitatsklinikum Bonn and 39 more.
Type: Journal Article | Journal: Biological psychiatry | Year: 2015

Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged 45 years. Replication of suggestive associations (p < 5 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 10(-10)) and replication cohorts (p = 5.65 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 10(-8), and rs6813517 [SPOCK3], p = 2.58 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.


News Article | January 6, 2016
Site: phys.org

Their insights could shed light on medical conditions that occur early in development, such as holes in the heart, which are caused by cells not moving to the right place as an embryo develops. Researchers who set out to learn how pigment cells behave in mice found that they move and multiply randomly during early development rather than follow instructions. Their findings contradict the existing theory that piebald patterns form on animals' coats because pigment cells move too slowly to reach all parts of the embryo before it is fully formed. The study, by mathematicians and geneticists, shows that there is no complicated cell-to-cell communication to send the cells in a particular direction. The same mathematical model could now be used to follow other types of cell during early development. Researchers at the Universities of Bath and Edinburgh, who carried out the study, say it could help them better understand conditions linked to early cell positioning. Dr Richard Mort, from the University of Edinburgh's Medical Research Council Human Genetics Unit said: ''We already know cells move through the developing skin to create pigment. We have discovered that they move and multiply at random which is not what was expected. Using a mathematical model we were then able to show that this simple process could explain piebald patterns.'' Dr Christian Yates a Mathematical Biologist from the University of Bath, added: "Piebald patterns can be caused by a faulty version of a gene called kit. What we have found is counter intuitive. Previously it was thought that the defective kit gene slowed cells down but instead we've shown that it actually reduces the rate at which they multiply. There are too few pigment cells to populate the whole of the skin and so the animal gets a white belly. In addition to kit, there are many other genes that can create piebald patterns, the mathematical model can explain piebald patterns regardless of the genes involved.'' The research is published in Nature Communications. Explore further: Study of zebrafish skin patterns shows cells chasing other cells around (w/ video)


Bem D.,University of Birmingham | Yoshimura S.-I.,University of Liverpool | Yoshimura S.-I.,Osaka University | Nunes-Bastos R.,University of Liverpool | And 33 more authors.
American Journal of Human Genetics | Year: 2011

Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277-279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration. © 2011 The American Society of Human Genetics. All rights reserved.

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