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GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized(More)
Transforming growth factor-β (TGF-β) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-β family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for(More)
Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches(More)
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in reward sensitivity and response inhibition. The relative contribution of these frontostriatal mechanisms to ADHD symptoms and their genetic determinants is largely unexplored. METHODS Using functional magnetic resonance imaging and genetic analysis of the monoamine(More)
The last 5 years have seen rapid progress in Parkinson’s disease (PD) genetics, with the publication of a series of large-scale genome wide association studies for PD, and evaluation of the roles of the LRRK2 and GBA genes in the aetiology of PD. We are beginning to develop a coherent picture of the interplay of Mendelian and non-Mendelian factors in PD.(More)
Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants(More)
Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted(More)
BACKGROUND defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large(More)
OBJECTIVE We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset. METHODS This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies.(More)
Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts(More)