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Although sociologists in Britain have debated the nature of their field's relationship with biology since the late nineteenth century, interest in the full range of responses has only grown in recent years. This paper contributes to the spirit of historical revisionism by turning to the work of the biologist and first director of UNESCO, Julian Huxley (1887–1975). Paying particular attention to the doctrine he called ‘scientific humanism’ and his ideas about a biosocial agenda separate from the priorities of biology itself, the paper uses historical tools to address a concern that has frequently cast a shadow over debates about biosocial science: does it interfere with the progressive agenda sociologists have traditionally seen themselves as contributing to? The paper argues that Huxley's work is evidence that biosocial science is compatible with progressive goals and that recent developments in biology mean it may be the ideal time to reconsider long-standing attitudes. [ABSTRACT FROM AUTHOR]

The human body is built up of millions of cells that together function as tissues and organs. Desmosomes are tiny structures on cell surfaces that enable cells not only to stick to their neighbours but also to communicate with them. Desmosomes in skin cells have been studied in detail partly because this organ is the most easily accessible to researchers. Also, mutations (mistakes) in the genes that code for the various protein components of desmosomes can cause serious life‐long skin problems such as blistering, fragility or excessive skin thickness. Some mutations affect desmosomes in the heart, causing life‐threatening problems such as sudden disturbance in heart rhythm. In this paper, researchers at a major UK dermatology centre review current knowledge of the desmosomal genes, proteins and diseases. Using clear diagrams, they summarize the roles of the three protein superfamilies involved: the cadherins (desmogleins and desmocollins); the armadillo proteins (plakoglobin plakophilin); and the plakin family (desmoplakin). Genetic disorders affecting the skin or mucous membranes (which line and protect, for example, the mouth, stomach and lungs) can be caused by mutations in any one of nine genes (DSG1, DSG3, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP); hair disorders can result from mutations in eight genes (DSG4, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP); mutations in three genes can cause syndromes affecting skin, hair and heart (DSC2, JUP, DSP) and mutations in five genes can cause heart problems without any abnormality in the skin or hair (DSG2, DSC2, JUP, PKP2, DSP). This knowledge will help dermatologists to advise patients with desmosomal skin and hair disorders. Linked Article: Lee and McGrath. Br J Dermatol 2021; 184:596–605. Linked Article: Lee and McGrath. Br J Dermatol 2021; 184:596–605. [ABSTRACT FROM AUTHOR]

Rare variant studies are now being used to characterize the genetic diversity between individuals and may help to identify substantial amounts of the genetic variation of complex diseases and quantitative phenotypes. Family data have been shown to be powerful to interrogate rare variants. Consequently, several rare variants association tests have been recently developed for family-based designs, but typically, these assume the normality of the quantitative phenotypes. In this paper, we present a family-based test for rare-variants association in the presence of non-normal quantitative phenotypes. The proposed model relaxes the normality assumption and does not specify any parametric distribution for the marginal distribution of the phenotype. The dependence between relatives is modeled via a Gaussian copula. A score-type test is derived, and several strategies to approximate its distribution under the null hypothesis are derived and investigated. The performance of the proposed test is assessed and compared with existing methods by simulations. The methodology is illustrated with an association study involving the adiponectin trait from the UK10K project. [ABSTRACT FROM AUTHOR]

The objective of this study was to detect and characterise the biovar of equine herpesvirus type 1 (EHV-1) from submandibular lymph nodes (SMLNs) and trigeminal ganglia from 153 equids undergoing routine postmortem examination for various medical and surgical reasons. A combination of nucleic acid precipitation and preamplification steps was used to increase the analytical sensitivity of the analysis. The presence of latent EHV-1 was determined when tissue samples were PCR-positive for the glycoprotein B (gB) gene and the DNA polymerase (ORF 30) gene of EHV-1 in the absence of detectable late structural protein gene (gB gene) mRNA. The SMLNs of five of the study animals (3.3 per cent) were PCR- positive for the gB gene of EHV-1. Two SMLNs carried a latent neurotropic strain of the virus, whereas three SMLNs were PCR-positive for both neurotropic and non-neurotropic EHV-1. A total of 30 trigeminal ganglia collected from 19 horses were PCR-positive for the gB gene of EHV-1. Nine trigeminal ganglia harboured either latent non-neurotropic or neurotropic EHV-1 strains. Twelve trigeminal ganglia contained both latent neurotropic and non-neurotropic EHV-1. The prevalence and distribution of EHV-1 biovars among the study horses appeared to be influenced by their breed and the type of tissue tested. [ABSTRACT FROM AUTHOR]

The relaxin-3/RXFP3 system has been implicated in the modulation of depressive- and anxiety-like behaviour in the animal literature; however, there is a lack of human studies investigating this signalling system. We seek to bridge this gap by leveraging the large UK Biobank study to retrospectively assess genetic risk variants linked with this neuropeptidergic system. Specifically, we conducted a candidate gene study in the UK Biobank to test for potential associations between a set of functional, candidate single nucleotide polymorphisms (SNPs) pertinent to relaxin-3 signalling, determined using in silico tools, and several outcomes, including depression, atypical depression, anxiety and metabolic syndrome. For each outcome, we used several rigorously defined phenotypes, culminating in subsample sizes ranging from 85,881 to 386,769 participants. Across all outcomes, there were no associations between any candidate SNP and any outcome phenotype, following corrections for multiple testing burden. Regression models comprising several SNPs per relevant candidate gene as exploratory variables further exhibited no prediction of outcome. Our findings corroborate conclusions from previous literature about the limitations of candidate gene approaches, even when based on firm biological hypotheses, in the domain of genetic research for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

We present here the use of targeted, long‐read sequencing of the myostatin (MSTN) gene as a model to detect potential gene editing events in Thoroughbred horses. MSTN is a negative regulator of muscle development, making the gene a prime candidate target for gene doping. By sequencing the complete gene in one PCR product, we can catalogue all mutations without the need to produce short‐fragment libraries. A panel of reference material fragments with defined mutations was constructed and successfully sequenced by both Oxford Nanopore and Illumina‐based methods, showing that gene doping editing events can be detected using this technology. To ascertain the normal variation within the population, we sequenced the MSTN gene in 119 UK Thoroughbred horses. Variants from the reference genome were assigned to haplotypes and eight distinct patterns, designated Hap1 (reference genome) to Hap8, were determined with haplotypes Hap2 and Hap3 (which includes the 'speed gene' variant) being far the most prevalent. Hap3 was most abundant in flat‐racing horses, whereas Hap2 was most abundant in jump‐racing. Within this data set, results for 105 racehorses from out‐of‐competition sampling were compared between matrices of extracted DNA and direct PCR of whole blood from lithium heparin gel tubes, and strong agreement was found between the two methods. The direct‐blood PCR was achieved without compromising the sample prior to plasma separation for analytical chemistry, and could thus be used as part of a routine screening workflow for gene editing detection. [ABSTRACT FROM AUTHOR]

Gene drive is an emerging biotechnology with applications in global health, conservation and agriculture. Scientists are preparing for field trials, triggering debate about when and how to release gene-drive organisms. These decisions depend on public understandings of gene drive, which are shaped by language. While some studies on gene drive communication assume the need to persuade publics of expert definitions of gene drive, we highlight the importance of meaning-making in communication and engagement. We conducted focus groups with humanities and science teachers in the United Kingdom and United States to explore how different media framings stimulated discussions of gene drive. We found diversity in the value of these framings for public debate. Interestingly, the definition favoured by gene drive scientists was the least popular among participants. Rather than carefully curating language, we need opportunities for publics to make sense and negotiate the meanings of a technology on their own terms. [ABSTRACT FROM AUTHOR]

Phenotypes of athletic performance and exercise capacity are complex traits influenced by both genetic and environmental factors. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status summarises recent advances in sports genomics research, including findings from candidate gene and genome-wide association (GWAS) studies, meta-analyses, and findings involving larger-scale initiatives such as the UK Biobank. As of the end of May 2023, a total of 251 DNA polymorphisms have been associated with athlete status, of which 128 genetic markers were positively associated with athlete status in at least two studies (41 endurance-related, 45 power-related, and 42 strength-related). The most promising genetic markers include the AMPD1 rs17602729 C, CDKN1A rs236448 A, HFE rs1799945 G, MYBPC3 rs1052373 G, NFIA-AS2 rs1572312 C, PPARA rs4253778 G, and PPARGC1A rs8192678 G alleles for endurance; ACTN3 rs1815739 C, AMPD1 rs17602729 C, CDKN1A rs236448 C, CPNE5 rs3213537 G, GALNTL6 rs558129 T, IGF2 rs680 G, IGSF3 rs699785 A, NOS3 rs2070744 T, and TRHR rs7832552 T alleles for power; and ACTN3 rs1815739 C, AR ≥21 CAG repeats, LRPPRC rs10186876 A, MMS22L rs9320823 T, PHACTR1 rs6905419 C, and PPARG rs1801282 G alleles for strength. It should be appreciated, however, that elite performance still cannot be predicted well using only genetic testing. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have discovered hundreds of associations between common genotypes and kidney function but cannot comprehensively investigate rare coding variants. Here, we apply a genotype imputation approach to whole exome sequencing data from the UK Biobank to increase sample size from 166,891 to 408,511. We detect 158 rare variants and 105 genes significantly associated with one or more of five kidney function traits, including genes not previously linked to kidney disease in humans. The imputation-powered findings derive support from clinical record-based kidney disease information, such as for a previously unreported splice allele in PKD2, and from functional studies of a previously unreported frameshift allele in CLDN10. This cost-efficient approach boosts statistical power to detect and characterize both known and novel disease susceptibility variants and genes, can be generalized to larger future studies, and generates a comprehensive resource (https://ckdgen-ukbb.gm.eurac.edu/) to direct experimental and clinical studies of kidney disease. An exome wide association study of UK Biobank data revealed 158 variants and 105 genes significantly associated with kidney function traits and disease. The findings are supported by functional evidence for a previously unreported mutation in CLDN10. [ABSTRACT FROM AUTHOR]

Background: Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods. Methods: The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient's diagnostic reports. Results: 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were "missed" by 100KGP standard analyses, which are now being returned to patients. Conclusion: We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered. [ABSTRACT FROM AUTHOR]

Introduction: Septoria tritici blotch (STB) is one of the most damaging fungal diseases of wheat in Europe, largely due to the paucity of effective resistance genes against it in breeding materials. Currently dominant protection methods against this disease, e.g. fungicides and the disease resistance genes already deployed, are losing their effectiveness. Therefore, it is vital that other available disease resistance sources are identified, understood and deployed in a manner that maximises their effectiveness and durability. Methods: In this study, we assessed wheat genotypes containing nineteen known major STB resistance genes (Stb1 through to Stb19) or combinations thereof against a broad panel of 93 UK Zymoseptoria tritici isolates. Seedlings were inoculated using a cotton swab and monitored for four weeks. Four infection-related phenotypic traits were visually assessed. These were the days post infection to the development of first symptoms and pycnidia, percentage coverage of the infected leaf area with chlorosis/necrosis and percentage coverage of the infected leaf area with pycnidia. Results: The different Stb genes were found to vary greatly in the levels of protection they provided, with pycnidia coverage at four weeks differing significantly from susceptible controls for every tested genotype. Stb10, Stb11, Stb12, Stb16q, Stb17, and Stb19 were identified as contributing broad spectrum disease resistance, and synthetic hexaploid wheat lines were identified as particularly promising sources of broadly effective STB resistances. Discussion: No single Z. tritici isolate was found to be virulent against all tested resistance genes. Wheat genotypes carrying multiple Stb genes were found to provide higher levels of resistance than expected given their historical levels of use. Furthermore, it was noted that disease resistance controlled by different Stb genes was associated with different levels of chlorosis, with high levels of early chlorosis in some genotypes correlated with high resistance to fungal pycnidia development, potentially suggesting the presence of multiple resistance mechanisms. The knowledge obtained here will aid UK breeders in prioritising Stb genes for future breeding programmes, in which optimal combinations of resistance genes could be pyramided. In addition, this study identified the most interesting Stb genes for cloning and detailed functional analysis. [ABSTRACT FROM AUTHOR]

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration. Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case–control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models. Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06–2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02–3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03–1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672–2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose–response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06–96.47, p = 0.007). Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants. [ABSTRACT FROM AUTHOR]

The cell adhesion molecule 2 (CADM2) gene has appeared among the top associations in a wide range of genome-wide association studies (GWASs). This study aims to: (1) examine how widespread the role of CADM2 is in behavioural traits, and (2) investigate trait-specific effects on CADM2 expression levels across tissues. We conducted a phenome-wide association study in UK Biobank (N = 12,211–453,349) on 242 psycho-behavioral traits, both at the SNP and the gene-level. For comparison, we repeated the analyses for other large (and high LD) genes. We found significant associations between CADM2 and 50 traits (including cognitive, risk taking, and dietary traits), many more than for the comparison genes. We show that many trait associations are reduced when taking geographical stratification into account. S-Predixcan revealed that CADM2 expression in brain tissues was significantly associated with many traits; highly significant effects were also observed for lung, mammary, and adipose tissues. In conclusion, this study shows that the role of CADM2 extends to a wide range of psycho-behavioral traits, suggesting these traits may share a common biological denominator. [ABSTRACT FROM AUTHOR]

Ever since twin-family studies found that a substantial amount (± 40%) of the variation in well-being can be explained by genetic variation, several candidate genes have been proposed explaining this variation. However, these candidate gene and candidate gene-by-environment interaction studies have been surrounded by controversy regarding the validity and replication of their results. In the present study, we review the existing candidate gene literature for well-being. First, we perform a systematic literature search that results in the inclusion of 41 studies. After describing the results of the included studies, we evaluated the included candidate polymorphisms by (1) looking up the results for the studied candidate SNPs in a large well-being genome-wide association study, (2) performing association analyses in UK biobank (UKB) data for the candidate variable number tandem repeats (VNTR) and the APOE ε4 allele, and (3) studying possible candidate interactions with positive and negative environmental moderators using UKB data. We find no support for any of the candidate genes or candidate gene-environment interactions for well-being, with the exception of two SNPs that were chosen based on genome-wide evidence. While the generalizability of our findings is limited by our phenotype and environment definitions, we strongly advise well-being researchers to abandon the candidate gene approach in the field of well-being and move toward genome-wide approaches. [ABSTRACT FROM AUTHOR]

Fertility, health, education, and other out comes of interest to demographers are the product of an individual's genetic makeup and their social environment. Yet, gene x environment (GxE) research deploys a limited toolkit on the genetic side to study the gene--environment interplay, relying on polygenic scores (PGSs) that reflect the influence of genetics on levels of an out come. In this article, we develop a genetic summary measure better suited for GxE research: variance poly genic scores (vPGSs), which are PGSs that reflect genetic contributions to plasticity in out comes. First, we use the UK Biobank (N ~ 408,000 in the analytic sample) and the Health and Retirement Study (N ~ 5,700 in the analytic sample) to compare four approaches to constructing PGSs for plasticity. The results show that widely used methods for discovering which genetic variants affect out come variability fail to serve as distinctive new tools for GxE. Second, using the PGSs that do capture distinctive genetic contributions to plasticity, we analyze heterogeneous effects of a UK education reform on health and educational attainment. The results show the properties of a useful new tool for population scientists studying the interplay of nature and nurture and for population-based studies that are releasing PGSs to applied researchers. [ABSTRACT FROM AUTHOR]

The article reports on a study which indicates that childhood obesity is caused by genetic factors. Researchers in Great Britain found that rare deletions on chromosome 16 (16p11.2) were prevalent in children who are obese as they looked at the copy number variations. Research author Sadaf Farooqi states that genetic variants can produce a strong drive to eat as shown in the study.

This paper reports on young people's understanding of genes as they near the end of their compulsory science education in the UK. A sample of 482 school students aged 14 - 16, drawn from across the ability range, took part in this study. Findings, based mainly on written responses to written questions, but supported by interview data, show that this sample had only a very limited understanding of the most basic ideas relating to function, structure, and location of genes. It is argued that these findings are not atypical for this population of school students. The implications for teaching the more complex genetic concepts demanded by the National Curriculum -- genetic engineering, for example w are considered. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution. Objective and methods: We performed a genome‐wide meta‐analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome‐wide association analysis linked T1D diagnosis age and gene expression. Results: We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene‐level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non‐HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non‐HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue. Conclusion: Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset. [ABSTRACT FROM AUTHOR]

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception. Author summary: Chronic pain is a highly prevalent and debilitating condition, which is more common in women than in men. Sex differences in this condition may be a result of several factors, including differences between the sexes in genetic variation related to chronic pain and gene expression differences related to sex. To explore sex differences in chronic pain from a genetic perspective, we looked for genetic variants associated with chronic pain in men and women separately in a large general-population cohort, and compared the variants we identified between the sexes. We assessed the degree of overlap between genetic variants associated with chronic pain in each sex and those associated with a wide range of other traits, including major depression, body-mass index and suicidality. We also investigated gene expression patterns across a range of tissues for genes associated with chronic pain in each sex, in particular examining expression in neural and non-neural human and mouse tissues and assessing the degree of Dorsal Root Ganglion (DRG) enrichment, an important peripheral nervous system component involved in chronic pain. This work contributes to understanding of chronic pain as a trait and of sex differences in chronic pain at the levels of genetics and gene expression. [ABSTRACT FROM AUTHOR]

Identifying genetic biomarkers for brain connectivity helps us understand genetic effects on brain function. The unique and important challenge in detecting associations between brain connectivity and genetic variants is that the phenotype is a matrix rather than a scalar. We study a new concept of super‐variant for genetic association detection. Similar to but different from the classic concept of gene, a super‐variant is a combination of alleles in multiple loci but contributing loci can be anywhere in the genome. We hypothesize that the super‐variants are easier to detect and more reliable to reproduce in their associations with brain connectivity. By applying a novel ranking and aggregation method to the UK Biobank databases, we discovered and verified several replicable super‐variants. Specifically, we investigate a discovery set with 16,421 subjects and a verification set with 2,882 subjects, where they are formed according to release date, and the verification set is used to validate the genetic associations from the discovery phase. We identified 12 replicable super‐variants on Chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 16, 18, and 19. These verified super‐variants contain single nucleotide polymorphisms that locate in 14 genes which have been reported to have association with brain structure and function, and/or neurodevelopmental and neurodegenerative disorders in the literature. We also identified novel loci in genes RSPO2 and TMEM74 which may be upregulated in brain issues. These findings demonstrate the validity of the super‐variants and its capability of unifying existing results as well as discovering novel and replicable results. [ABSTRACT FROM AUTHOR]

Conventional human leukocyte antigen (HLA) imputation methods drop their performance for infrequent alleles, which is one of the factors that reduce the reliability of trans-ethnic major histocompatibility complex (MHC) fine-mapping due to inter-ethnic heterogeneity in allele frequency spectra. We develop DEEP*HLA, a deep learning method for imputing HLA genotypes. Through validation using the Japanese and European HLA reference panels (n = 1,118 and 5,122), DEEP*HLA achieves the highest accuracies with significant superiority for low-frequency and rare alleles. DEEP*HLA is less dependent on distance-dependent linkage disequilibrium decay of the target alleles and might capture the complicated region-wide information. We apply DEEP*HLA to type 1 diabetes GWAS data from BioBank Japan (n = 62,387) and UK Biobank (n = 354,459), and successfully disentangle independently associated class I and II HLA variants with shared risk among diverse populations (the top signal at amino acid position 71 of HLA-DRβ1; P = 7.5 × 10−120). Our study illustrates the value of deep learning in genotype imputation and trans-ethnic MHC fine-mapping. Human leukocyte antigen (HLA) genes contribute to risk of many complex traits, yet understanding inter-ethnic heterogeneity is computationally challenging. Here, the authors develop DEEP*HLA for imputation of HLA genotypes and show its ability to disentangle HLA variant risk effects in diverse populations. [ABSTRACT FROM AUTHOR]

Background: The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. Objectives: We performed a genome‐wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. Methods: Facial telangiectasia were extracted from standardized facial photographs (collected from 2010–2013) of 2842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (P‐value <10−6) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP‐based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin colour was additionally performed. Results: Our most significant GWAS signal was rs4417318 (P‐value 5.38*10−7), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin colour. Conclusion: In this GWAS on telangiectasia in a northwestern European population, no genome‐wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin colour and telangiectasia. [ABSTRACT FROM AUTHOR]

Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition. [ABSTRACT FROM AUTHOR]

Background: The incidence of colorectal cancer (CRC) is increasing in developing countries, yet limited research on the CRC- associated microbiota has been conducted in these areas, in part due to scarce resources, facilities, and the difficulty of fresh or frozen stool storage/transport. Here, we aimed (1) to establish a broad representation of diverse developing countries (Argentina, Chile, India, and Vietnam); (2) to validate a 'resource-light' sample-collection protocol translatable in these settings using guaiac faecal occult blood test (gFOBT) cards stored and, importantly, shipped internationally at room temperature; (3) to perform initial profiling of the collective CRC-associated microbiome of these developing countries; and (4) to compare this quantitatively with established CRC biomarkers from developed countries. Methods: We assessed the effect of international storage and transport at room temperature by replicating gFOBT from five UK volunteers, storing two in the UK, and sending replicates to institutes in the four countries. Next, to determine the effect of prolonged UK storage, DNA extraction replicates for a subset of samples were performed up to 252 days apart. To profile the CRC-associated microbiome of developing countries, gFOBT were collected from 41 treatment-naïve CRC patients and 40 non-CRC controls from across the four institutes, and V4 16S rRNA gene sequencing was performed. Finally, we constructed a random forest (RF) model that was trained and tested against existing datasets from developed countries. Results: The microbiome was stably assayed when samples were stored/transported at room temperature and after prolonged UK storage. Large-scale microbiome structure was separated by country and continent, with a smaller effect from CRC. Importantly, the RF model performed similarly to models trained using external datasets and identified similar taxa of importance (Parvimonas, Peptostreptococcus, Fusobacterium, Alistipes, and Escherichia). Conclusions: This study demonstrates that gFOBT, stored and transported at room temperature, represents a suitable method of faecal sample collection for amplicon-based microbiome biomarkers in developing countries and suggests a CRC-faecal microbiome association that is consistent between developed and developing countries. [ABSTRACT FROM AUTHOR]

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism. Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease. [ABSTRACT FROM AUTHOR]

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference. The genetic basis of daytime napping and the directional effect of daytime napping on cardiometabolic health are unknown. Here, the authors perform a genome-wide association study on self-reported daytime napping in the UK Biobank and Mendelian randomization to explore causal associations. [ABSTRACT FROM AUTHOR]

Traditional univariate genome-wide association studies generate false positives and negatives due to difficulties distinguishing associated variants from variants with spurious nonzero effects that do not directly influence the trait. Recent efforts have been directed at identifying genes or signaling pathways enriched for mutations in quantitative traits or case-control studies, but these can be computationally costly and hampered by strict model assumptions. Here, we present gene-ε, a new approach for identifying statistical associations between sets of variants and quantitative traits. Our key insight is that enrichment studies on the gene-level are improved when we reformulate the genome-wide SNP-level null hypothesis to identify spurious small-to-intermediate SNP effects and classify them as non-causal. gene-ε efficiently identifies enriched genes under a variety of simulated genetic architectures, achieving greater than a 90% true positive rate at 1% false positive rate for polygenic traits. Lastly, we apply gene-ε to summary statistics derived from six quantitative traits using European-ancestry individuals in the UK Biobank, and identify enriched genes that are in biologically relevant pathways. Author summary: Enrichment tests augment the standard univariate genome-wide association (GWA) framework by identifying groups of biologically interacting mutations that are enriched for associations with a trait of interest, beyond what is expected by chance. These analyses model local linkage disequilibrium (LD), allow many different mutations to be disease-causing across patients, and generate biologically interpretable hypotheses for disease mechanisms. However, existing enrichment analyses are hampered by high computational costs, and rely on GWA summary statistics despite the high false positive rate of the standard univariate GWA framework. Here, we present the gene-level association framework gene-ε (pronounced "genie"), an empirical Bayesian approach for identifying statistical associations between sets of mutations and quantitative traits. The central innovation of gene-ε is reformulating the GWA null model to distinguish between (i) mutations that are statistically associated with the disease but are unlikely to directly influence it, and (ii) mutations that are most strongly associated with a disease of interest. We find that, with our reformulated SNP-level null hypothesis, our gene-level enrichment model outperforms existing enrichment methods in simulation studies and scales well for application to emerging biobank datasets. We apply gene-ε to six quantitative traits in the UK Biobank and recover novel and functionally validated gene-level associations. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perform a transcriptome-wide association study to identify associations with gene expression in relevant tissues, identifying 66 associated genes across the three traits. This genetic study provides insights into the understanding of the biological mechanisms underlying small vessel disease. Cerebral small vessel disease (CSVD) is a major cause of stroke and associated with structural changes of the brain. Here, Persyn et al. perform genome-wide association studies for magnetic resonance imaging (MRI) markers of CSVD, explore genetic correlations and prioritize candidate genes. [ABSTRACT FROM AUTHOR]

Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants. Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity. [ABSTRACT FROM AUTHOR]

Individual seed saving and exchange are considered important components of contemporary efforts to conserve crop genetic diversity that ramify at local, regional, and global scales. Yet the very fact that the contributions of these activities to conservation need to be made explicit by seed savers and those who study them indicates that the practices of seed saving and exchange may not immediately be recognized as conservation‐oriented activities. This article investigates why and how individual seed saving came to be aligned with a broader conservation agenda in Britain through a historical examination of the promotion of seed saving by the Henry Doubleday Research Association (HDRA) in the 1970s and 1980s. It demonstrates how several HDRA initiatives that aimed to preserve vegetable diversity also re‐inscribed British gardeners' ordinary labor as conservation work. This historical study complements sociological and ethnographic studies, highlighting the role of a prominent organization in creating pathways for individuals to engage in local, national, and international conservation through seed saving. It also serves as a reminder that the connections between these activities had to be made explicit—that is, that there was (and is) work involved in connecting individual acts of seed saving to conservation outcomes at different scales. [ABSTRACT FROM AUTHOR]

We hypothesized that monogenic syndromic obesity genes are also involved in the polygenic variation of BMI. Single-marker, tag single nucleotide polymorphism (tagSNP) and gene-based analysis were performed on common variants near 54 syndromic obesity genes. We used publicly available data from meta-analyses of European BMI genome-wide association studies conducted by the Genetic Investigation of ANthropometric Traits (GIANT) Consortium and the UK Biobank (UKB) (N = 681,275 adults). A total of 33 loci were identified, of which 19 of 33 (57.6%) were located at SNPs previously identified by the GIANT Consortium and UKB meta-analysis, 11 of 33 (33.3%) were located at novel SNPs, and 3 of 33 (9.1%) were novel genes identified with gene-based analysis. Both single-marker and tagSNP analyses mapped the previously identified 19 SNPs by the GIANT Consortium and UKB meta-analysis. Gene-based analysis confirmed 15 of 19 (78.9%) of the novel SNPs' associated genes. Of the 11 novel loci, 8 were identified with single-marker analysis and the remaining 3 were identified with tagSNP analysis. Gene-based analysis confirmed 4 of 11 (36.3%) of these loci. Meta-analysis with the Early Growth Genetics (EGG) Consortium (N = 35,668 children) was conducted post hoc for top SNPs, confirming 17 of 33 (51.5%) loci, of which 5 were novel. This study supports evidence for a continuum between rare monogenic syndromic and common polygenic forms of obesity. [ABSTRACT FROM AUTHOR]

Objectives: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function.Methods: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia.Results: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage.Conclusions: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.Clinical Trial Registration: NCT02881099; Results. [ABSTRACT FROM AUTHOR]

Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome- wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS (P = 1.53 × 10-10) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Conduct problems (CP) and attention deficit hyperactivity disorder (ADHD) are often comorbid and have each been linked to 'unhealthy diet'. Early-life diet also associates with DNA methylation of the insulin-like growth factor 2 gene (IGF2), involved in fetal and neural development. We investigated the degree to which prenatal high-fat and -sugar diet might relate to ADHD symptoms via IGF2 DNA methylation for early-onset persistent (EOP) versus low CP youth. Methods: Participants were 164 youth with EOP (n = 83) versus low (n = 81) CP drawn from the Avon Longitudinal Study of Parents and Children. We assessed if the interrelationships between high-fat and -sugar diet (prenatal, postnatal), IGF2 methylation (birth and age 7, collected from blood), and ADHD symptoms (age 7-13) differed for EOP versus low CP youth. Results: Prenatal 'unhealthy diet' was positively associated with IGF2 methylation at birth for both the EOP and low CP youth. For EOP only: (a) higher IGF2 methylation predicted ADHD symptoms; and (b) prenatal 'unhealthy diet' was associated with higher ADHD symptoms indirectly via higher IGF2 methylation. Conclusions: Preventing 'unhealthy diet' in pregnancy might reduce the risk of ADHD symptoms in EOP youth via lower offspring IGF2 methylation. [ABSTRACT FROM AUTHOR]

Objective: With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids.Methods: Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores.Results: On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively.Conclusions: Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia, anterior frontal and parietal cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest clinical duration had an atypical synaptic deposition of abnormal prion protein and no kuru plaques. Taken together, these data provide a remarkable example of the interplay between the strain of the pathogen and host prion protein genotype. Based on extensive modelling of human prion transmission barriers in transgenic mice expressing human prion protein on a mouse prion protein null background, the temporal distribution of codon 129 genotypes within the cohort of patients with iatrogenic Creutzfeldt-Jakob disease in the UK suggests that there was a point source of infecting prion contamination of growth hormone derived from a patient with Creutzfeldt-Jakob disease expressing prion protein valine 129. [ABSTRACT FROM AUTHOR]

Background: circulating measures of inflammatory markers, such as C-reactive protein (CRP) have been associated with an increased risk of future cognitive decline. However, the nature of the relationship among the very old (>75 years) is unclear. Cross-sectional evidence suggests that elevated CRP may even be protective in this age group. This study examines these associations longitudinally.Methods: logistic regression was used to investigate the association between CRP and drop in cognitive performance (≥3 point change on the Mini-Mental State Examination) over a 4-year period in a population of 266 people, mean age 77 years.Results: increased levels of CRP were associated with a decreased risk of a drop in cognitive performance; however, this association was only seen in those without an APOE e4 allele [odds ratio of decline per unit increase in ln(CRP) 0.57, P = 0.04]. The magnitude of the finding remained consistent after adjustment for cardiovascular confounders (smoking, drinking, MI, stroke, diabetes, education, medication and blood pressure). For those with an e4 allele, the relationship with longitudinal cognitive decline was neither statistically significant nor in a consistent direction after controlling for acute inflammation.Conclusions: this study strengthens previous cross-sectional findings and shows elevated levels of CRP to be linked to a decreased risk of longitudinal cognitive decline in the very old. However, as with prior analyses, this was only observed in those not carrying an APOE e4 allele. Future work on larger APOE e4 allele carrying samples is required to determine the nature of the association in this population. [ABSTRACT FROM AUTHOR]

Background The low expression polymorphism of the MAOA gene in interaction with adverse environments (G × E) is associated with antisocial behaviour disorders. These have their origins in early life, but it is not known whether MAOA G × E occurs in infants. We therefore examined whether MAOA G × E predicts infant anger proneness, a temperamental dimension associated with later antisocial behaviour disorders. In contrast to previous studies, we examined MAOA G × E prospectively using an observational measure of a key aspect of the infant environment, maternal sensitivity, at a specified developmental time point. Methods In a stratified epidemiological cohort recruited during pregnancy, we ascertained MAOA status (low vs. high expression alleles) from the saliva of 193 infants, and examined specific predictions to maternal report of infant temperament at 14 months from maternal sensitivity assessed at 29 weeks of age. Results Analyses, weighted to provide general population estimates, indicated a robust interaction between MAOA status and maternal sensitivity in the prediction of infant anger proneness ( p = .003) which became stronger once possible confounders for maternal sensitivity were included in the model ( p = .0001). The interaction terms were similar in males ( p = .010) and females ( p = .016), but the effects were different as a consequence of an additional sex of infant by maternal sensitivity interaction. Conclusions This prospective study provides the first evidence of moderation by the MAOA gene of effects of parenting on infant anger proneness, an important early risk for the development of disruptive and aggressive behaviour disorders. [ABSTRACT FROM AUTHOR]

Objectives We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor ( NNRTI) administered with zidovudine ( ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non- TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non- TA group). Methods Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non- TA. Results A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non- TA. No significant differences were observed between the non- TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log10 copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors ( RTIs) occurred at a significant lower frequency in the non- TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor ( NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non- TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non- TA group (18.5%; P < 0.001). Conclusions At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non- TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure. [ABSTRACT FROM AUTHOR]

Complete skulls of giant marine reptiles of the Late Jurassic are rare, and so the discovery of the 1.8-m-long skull of a pliosaur from the Kimmeridge Clay Formation (Kimmeridgian) of Westbury, Wiltshire, UK, is an important find. The specimen shows most of the cranial and mandibular anatomy, as well as a series of pathological conditions. It was previously referred to Pliosaurus brachyspondylus, but it can be referred reliably only to the genus Pliosaurus, because species within the genus are currently in need of review. The new specimen, together with another from the same locality, also referred to P. brachyspondylus, will be crucial in that systematic revision, and it is likely that the genus Pliosaurus will be found to include several genera. The two Westbury Pliosaurus specimens share many features, including the form of the teeth, but marked differences in the snout and parietal crest suggest sexual dimorphism; the present specimen is probably female. The large size of the animal, the extent of sutural fusion and the pathologies suggest this is an ageing individual. An erosive arthrotic condition of the articular glenoids led to prolonged jaw misalignment, generating a suite of associated bone and dental pathologies. Further damage to the jaw joint may have been the cause of death. [ABSTRACT FROM AUTHOR]

The common inheritance of approximately 20000 genes defines each of us as human. However, substantial variation exists between individual human genomes, including 'replication' of gene sequences (copy number variation, tandem repeats), or changes in individual base pairs (mutations if <1% fre- quency and single nucleotide polymorphisms if>l% frequency). A vast array of human phenotypes (e.g. muscle strength, skeletal structure, tendon elasticity, and heart and lung size) influences sports performance, each itself the result of a complex interaction between a myriad of anatomical, biochemical and physiological systems. This article discusses the role for genetic influences in influencing sporting performance and injury, offering specific exemplars where these are known. Many of these preferable genotypes are uncommon, and their combination even rarer. In theory, the chances of an individual having a perfect sporting genotype are much lower than 1 in 20 million-as the number of associated polymorphisms increase, the odds decrease correspondingly. Many recently discovered polymorphisms that may affect sports performance have been described in animal or other human based models, and have been included in this review if they may apply to athletic populations. Muscle performance is heavily influenced by basal muscle mass and its dy- namic response to training. Genetic factors account for approximately 50-80% of inter-individual variation in lean body mass, with impacts detected on both 'training-naive' muscle mass and its growth response. Several cyto- kines such as interleukin-6 and -15, cilliary neurotrophic factor and insulin- like growth factor (IGF) have myoanabolic effects. Genotype-associated differences in endocrine function, necessary for normal skeletal muscle growth and function, may also be of significance, with complex interactions existing between thyroxine, growth hormone and the downstream regulators of the anabolic pathways (such as IGF-l and IGF-2). Almost 200 poly- morphisms are known to exist in the vitamin D receptor (VDR) gene. VDR genotype is associated with differences in strength in premenopausal women. VDR expression decreases with age and VDR genotype is associated with fat- free mass and strength in elderly men and women. Muscle fibre type de- termination is complex. Whilst initial composition is likely to be strongly influenced by genetic factors, training has significant effects on fibre shifts. Polymorphisms of the peroxisome proliferator-activated receptor a (PPARa) gene and R577x polymorphism of the A CTN3 gene are both associated with specific fibre compositions. Alterations in cardiac size have been associated with both increased performance and excess cardiovascular mortality. PPARca is a ligand-activated transcription factor that regulates genes involved in fatty acid uptake and oxidation, lipid metabolism and inflammation. Psychology plays an important role in training, competition, tolerance of pain and motivation. However, the role of genetic variation in determining psychological state and responses remains poorly understood; only recently have specific genes been implicated in motivational behaviour and maintenance of exercise. Thyroid hormone receptors exist within the brain and influence both neurogenesis and behaviour. With the current state of knowledge, the field of genetic influences on sports performance remains in its infancy, despite over a decade of research. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to estimate the levels of transmitted drug resistance (TDR) in HIV-1 using very sensitive assays to detect minority drug-resistant populations. Methods We tested unlinked anonymous serum specimens from sexual health clinic attendees, who had not received an HIV diagnosis at the time of sampling, by both standard genotyping and using minority detection assays. Results By standard genotyping, 21 of 165 specimens (12.7%) showed evidence of drug resistance, while, using a combination of standard genotyping and minority mutation assays targeting three commonly observed drug resistance mutations which cause high-level resistance to commonly prescribed first-line antiretroviral therapy (ART), this rose to 32 of 165 (19.4%). This increase of 45% in drug resistance levels [95% confidence interval (CI) 15.2-83.7%; P50.002] was statistically significant. Almost all of this increase was accounted for by additional detections of the M184V mutation. Conclusions Future surveillance studies of TDR in the United Kingdom should consider combining standard genotyping and minority-specific assays to provide more accurate estimates, particularly when using specimens collected from chronic HIV infections in which TDR variants may have declined to low levels. [ABSTRACT FROM AUTHOR]

Background: The circadian locomotor output cycles kaput (CLOCK) gene encodes protein regulation circadian rhythm and also plays some roles in neural transmitter systems including the dopamine system. Several lines of evidence implicate a relationship between attention-deficit hyperactivity disorder (ADHD), circadian rythmicity and sleeping disturbances. A recent study has reported that a polymorphism (rs1801260) at the 3'-untranslated region of the CLOCK gene is associated with adult ADHD. Methods: To investigate the association between the polymorphism (rs1801260) in ADHD, two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped and analysed using withinfamily transmission disequilibrium test (TDT). Bonferroni correction procedures were used to just for multiple comparisons. Results: We found evidence of increased transmission of the T allele of the rs1801260 polymorphism in Taiwanese samples (P = 0.010). There was also evidence of preferential transmission of the T allele of the rs1801260 polymorphism in combined samples from the Taiwan and UK (P = 0.008). Conclusion: This study provides evidence for the possible involvement of CLOCK in susceptibility to ADHD. [ABSTRACT FROM AUTHOR]

Background: The human death-associated protein 3 (hDAP3) is a GTP-binding constituent of the small subunit of the mitochondrial ribosome with a pro-apoptotic function.Methods: A search through publicly available microarray data sets showed 337 genes potentially coregulated with the DAP3 gene. The promoter sequences of these 337 genes and 70 out of 85 mitochondrial ribosome genes were analysed in silico with the DAP3 gene promoter sequence. The mitochondrial role of DAP3 was also investigated in the thyroid tumours presenting various mitochondrial contents.Results: The study revealed nine transcription factors presenting enriched motifs for these gene promoters, five of which are implicated in cellular growth (ELK1, ELK4, RUNX1, HOX11-CTF1, TAL1-ternary complex factor 3) and four in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), GABPA, PPARG-RXRA and estrogen-related receptor alpha (ESRRA)). An independent microarray data set showed the overexpression of ELK1, RUNX1 and ESRRA in the thyroid oncocytic tumours. Exploring the thyroid tumours, we found that DAP3 mRNA and protein expression is upregulated in tumours presenting a mitochondrial biogenesis compared with the normal tissue. ELK1 and ESRRA were also showed upregulated with DAP3.Conclusion: ELK1 and ESRRA may be considered as potential regulators of the DAP3 gene expression. DAP3 may participate in mitochondrial maintenance and play a role in the balance between mitochondrial homoeostasis and tumourigenesis. [ABSTRACT FROM AUTHOR]

Background: Epigenetic silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre.Methods: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas.Results: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS.Conclusions: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification. [ABSTRACT FROM AUTHOR]

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC. [ABSTRACT FROM AUTHOR]

The proteasome system is a proteolytic pathway that regulates the expression of genes involved in inflammation. Polymorphisms in the gene encoding subunit α type 6 (PSMA6) – in particular the rs1048990 exon 1–8C/G SNP – have been implicated with susceptibility to myocardial infarction (MI) in a Japanese study. We examined whether several polymorphisms in the PSMA6 gene were related to MI risk in 6946 nonfatal MI cases and 2720 unrelated controls in a UK population. The homozygous GG genotype for rs1048990 was much less frequent in this UK population than in the Japanese population (2.1 vs 8.9%), and was associated with an odds ratio (OR) for MI of 1.09 (95% confidence interval (CI): 0.98–1.21) per G allele in a co-dominant genetic model and 1.32 (95% CI: 0.90–1.93) in a recessive genetic model. Although not statistically significant, these results for this variant are still consistent with the Japanese hypothesis-generating study. Our findings, when taken together with four other studies (including the hypothesis-generating one), yielded a combined OR for MI of 1.15 (95% CI: 1.08–1.21) per G allele in a co-dominant model and 1.38 (95% CI: 1.22–1.57) for the GG genotype in a recessive model. Larger studies involving more than 10 000 disease cases would be required to further elucidate the role of this variant for susceptibility to MI. However, given the rarity of this variant in Caucasians, the attributable risk of rs1048990 for MI is unlikely to be great in western populations.European Journal of Human Genetics (2008) 16, 480–486; doi:10.1038/sj.ejhg.5201948; published online 30 January 2008 [ABSTRACT FROM AUTHOR]

Background: Part of the inherited risk to lung cancer is likely to include common, low risk alleles. The identification of this class of susceptibility is contingent on association-based analyses. We established GEnetic Lung CAncer Predisposition Study (GELCAPS) to collect DNA and clinicopathological data from a large series of cases and a series of spouse/partner controls, thereby generating a key resource for the identification of low risk alleles. Methods: GELCAPS was one of the first genetic epidemiological trials in the UK to be adopted by the National Cancer Research Network (NCRN) onto its portfolio with the participation of over 100 oncology departments specialising in the management of lung cancer. Results: Samples from over 5,000 independent lung cancer cases and 2,000 controls have so far been assembled through GELCAPS. Conclusion: GELCAPS represents one of the largest datasets of its type in the world capable of informing on the contribution of low penetrance alleles to the development of lung cancer and the influence of genetic variation on outcome. In addition our experience in developing the GELCAPS serves to illustrate how large DNA biobanks for genetic analyses can be rapidly generated within the UK using the NCRN. [ABSTRACT FROM AUTHOR]