👤 P J Schofield

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to analyze the genotype distribution of FCS-causing genes in the United Kingdom. Data were anonymously collated from 2 genetic testing laboratories providing national genetic diagnosis services for severe hypertriglyceridemia in the United Kingdom. As of December 2023, 880 individuals underwent genetic testing for FCS. The mean (SD) age at the time of genetic testing was 42.5 (15.3) years. After genotyping, 12.9% of the individuals ( The genetic architecture of FCS in the United Kingdom is complex, with a substantial proportion affected by non- Show less

RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5' UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons. Show less

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56-105 using immunoassays and explored relationships with APOE polymorphism ε2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE ε4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE ε4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals. Show less

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C. Show less

Carbamyl Phosphate Synthetase I (CPS1) (EC 6.3.4.16) is a highly conserved mitochondrial enzyme catalyzing the first committed step of waste nitrogen metabolism in the urea cycle. Using FISH for physical mapping and CEPH families for linkage analysis, we mapped the CPS1 gene (CPS1) to 2q34-->q35, reassigning it from 2p where it was originally mapped. Show less