To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Depression is a clinically heterogeneous disorder. Previous large-scale genetic studies of depression have explored genetic risk factors of depression case–control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.
We analyse data from 148 752 subjects of white British ancestry in the UK Biobank who completed nine items of a self-rated measure of current depressive symptoms: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD Score Regression was used to calculate SNP-based heritability (h2SNP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Genomic structural equation modelling was used to test the genetic factor structure across the nine symptoms.
We identified nine genome-wide significant genomic loci (8 novel), with no overlap in loci across symptoms. h2SNP ranged from 6% (concentration problems) to 9% (appetite changes). Genetic correlations ranged from 0.54 to 0.96 (all p < 1.39 × 10−3) with 30 of 36 correlations being significantly smaller than one. A two-factor model provided the best fit to the genetic covariance matrix, with factors representing ‘psychological’ and ‘somatic’ symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.
Patterns of SNP associations and genetic correlations differ across the nine symptoms, suggesting that current depressive symptoms are genetically heterogeneous. Our study highlights the value of symptom-level analyses in understanding the genetic architecture of a psychiatric trait. Future studies should investigate whether genetic heterogeneity is recapitulated in clinical symptoms of major depression.
Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.
Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).
Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation.
This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
Background. Frequency and quantity of alcohol consumption are metrics commonly used to measure alcohol consumption behaviors. Epidemiological studies indicate that these alcohol consumption measures are differentially associated with (mental) health outcomes and socioeconomic status (SES). The current study aims to elucidate to what extent genetic risk factors are shared between frequency and quantity of alcohol consumption, and how these alcohol consumption measures are genetically associated with four broad phenotypic categories: (i) SES; (ii) substance use disorders; (iii) other psychiatric disorders; and (iv) psychological/personality traits.
Methods. Genome-Wide Association analyses were conducted to test genetic associations with alcohol consumption frequency (N = 438 308) and alcohol consumption quantity (N = 307 098 regular alcohol drinkers) within UK Biobank. For the other phenotypes, we used genome-wide association studies summary statistics. Genetic correlations (rg) between the alcohol measures and other phenotypes were estimated using LD score regression.
Results. We found a substantial genetic correlation between the frequency and quantity of alcohol consumption (rg = 0.52). Nevertheless, both measures consistently showed opposite genetic correlations with SES traits, and many substance use, psychiatric, and psychological/personality traits. High alcohol consumption frequency was genetically associated with high SES and low risk of substance use disorders and other psychiatric disorders, whereas the opposite applies for high alcohol consumption quantity.
Conclusions. Although the frequency and quantity of alcohol consumption show substantial genetic overlap, they consistently show opposite patterns of genetic associations with SES-related phenotypes. Future studies should carefully consider the potential influence of SES on the shared genetic etiology between alcohol and adverse (mental) health outcomes.
Following pioneering work in Norway, cirque glaciers have widely been viewed as rigidly rotating bodies. This model is incorrect for basin-filling cirque glaciers, as we have demonstrated at West Washmawapta Glacier, a small glacier in the Canadian Rocky Mountains. Here we report observations at the same glacier that assess whether complex temporal variations of flow also occur. For parts of three summers, we measured daily displacements of the glacier surface. In one year, four short-duration speed-up events were recorded. Three of the events occurred during the intervals of warmest weather, when melt was most rapid; the fourth event occurred immediately following heavy rain. We interpret the speed-up events as manifestations of enhanced water inputs to the glacier bed and associated slip lubrication by increased water volumes and pressures. No further speed-ups occurred in the final month of the melt season, despite warm temperatures and several rainstorms; the dominant subglacial water system likely transformed from one of poorly connected cavities to one with an efficient channel network. The seasonal evolution of hydrology and flow resembles behaviors documented at other, larger temperate glaciers and indicates that analyses of cirque erosion cannot rely on simple assumptions about ice dynamics.
To study the salt and sugars content of breakfast cereals sold in the UK between 1992 and 2015.
Cross-sectional surveys on salt and sugars content collected from the nutrition information panel of breakfast cereals in 1992, 2004, 2006, 2009, 2012 and 2015.
All major UK retailers operating at that moment in time (approximately ten).
The salt and sugars content was collected from product packaging and the nutrition information panels.
Cereals consistently surveyed across all five years (n22) showed a significant reduction in salt content of 47 % (P<0·001). Sugars content of breakfast cereals (n 15), however, did not show a significant change; 25·65 g/100 g in 1992 and 22·45 g/100 g in 2015 (P=0·170). There was a large variation in salt and sugars content between different categories and within the same type of category.
The study shows the progressive reduction in salt content of breakfast cereals in the UK since 2004 as a result of the successful salt reduction programme, particularly the setting of incremental salt targets. Further reductions in salt content need to be made as cereals remain a major contributor to salt intake. Sugars content, however, has been consistently high due to the lack of a sugar reduction strategy. The research demonstrates that the sugars content of breakfast cereals in the UK is of concern, particularly in children’s breakfast cereals, with a typical serving (30 g) containing a third of a 4–6-year-old’s maximum daily recommendation (19 g/d) for free sugars intake in the UK. More can and should be done to reformulate, with an urgent need to set incremental sugar reduction targets.
Several airborne radar-sounding surveys are used to trace internal reflections around the European Project for Ice Coring in Antarctica Dome C and Vostok ice core sites. Thirteen reflections, spanning the last two glacial cycles, are traced within 200 km of Dome C, a promising region for million-year-old ice, using the University of Texas Institute for Geophysics High-Capacity Radar Sounder. This provides a dated stratigraphy to 2318 m depth at Dome C. Reflection age uncertainties are calculated from the radar range precision and signal-to-noise ratio of the internal reflections. The radar stratigraphy matches well with the Multichannel Coherent Radar Depth Sounder (MCoRDS) radar stratigraphy obtained independently. We show that radar sounding enables the extension of ice core ages through the ice sheet with an additional radar-related age uncertainty of ~1/3–1/2 that of the ice cores. Reflections are extended along the Byrd-Totten Glacier divide, using University of Texas/Technical University of Denmark and MCoRDS surveys. However, core-to-core connection is impeded by pervasive aeolian terranes, and Lake Vostok's influence on reflection geometry. Poor radar connection of the two ice cores is attributed to these effects and suboptimal survey design in affected areas. We demonstrate that, while ice sheet internal radar reflections are generally isochronal and can be mapped over large distances, careful survey planning is necessary to extend ice core chronologies to distant regions of the East Antarctic ice sheet.
Food liking-disliking patterns may strongly influence food choices and health. Here we assess: (1) whether food preference patterns are genetic/environmentally driven; and (2) the relationship between metabolomics profiles and food preference patterns in a large population of twins. 2,107 individuals from TwinsUK completed an online food and lifestyle preference questionnaire. Principle components analysis was undertaken to identify patterns of food liking-disliking. Heritability estimates for each liking pattern were obtained by structural equation modeling. The correlation between blood metabolomics profiles (280 metabolites) and each food liking pattern was assessed in a subset of 1,491 individuals and replicated in an independent subset of monozygotic twin pairs discordant for the liking pattern (65 to 88 pairs). Results from both analyses were meta-analyzed. Four major food-liking patterns were identified (Fruit and Vegetable, Distinctive Tastes, Sweet and High Carbohydrate, and Meat) accounting for 26% of the total variance. All patterns were moderately heritable (Fruit and Vegetable, h2[95% CI]: 0.36 [0.28; 0.44]; Distinctive Tastes: 0.58 [0.52; 0.64]; Sweet and High Carbohydrate: 0.52 [0.45, 0.59] and Meat: 0.44 [0.35; 0.51]), indicating genetic factors influence food liking-disliking. Overall, we identified 14 significant metabolite associations (Bonferroni p < 4.5 × 10−5) with Distinctive Tastes (8 metabolites), Sweet and High Carbohydrate (3 metabolites), and Meat (3 metabolites). Food preferences follow patterns based on similar taste and nutrient characteristics and these groupings are strongly determined by genetics. Food preferences that are strongly genetically determined (h2 ≥ 0.40), such as for meat and distinctive-tasting foods, may influence intakes more substantially, as demonstrated by the metabolomic associations identified here.
Age-related hearing impairment (ARHI) is a common condition with complex etiology but a recognized genetic component. Heritability estimates for pure tone audiogram-determined hearing ability lie in the range 26–75%. The speech-in-noise (SIN) auditory test, however, may be better at encapsulating ARHI symptoms, particularly the diminished ability to segregate environmental sounds into comprehendible auditory streams. As heritability of SIN has not previously been reported, we explored the genetic and environmental contributions to ARHI determined by SIN in 2,076 twins (87.8% female) aged 18–87 (mean age 54.4). SIN was found to be significantly heritable (A, unadjusted for age = 40%; 95% confidence intervals, CI = 32%–47%). With age adjustment, heritability fell (A = 25%; 95% CI = 16–33%), and a relatively strong influence of environmental exposure unshared within twin siblings was identified (E = 75%). To explore the environmental aspects further, we assessed the influence of diet (through the Food Frequency Questionnaire, FFQ), smoking (through self-report and cotinine metabolite levels) and alcohol intake (through the FFQ). A negative influence of high cholesterol diet was observed after adjustment (p = .037). A protective effect of raised serum high-density lipoprotein (HDL) cholesterol levels was observed after adjustment (p = .004). This study is the first assessment of the genetic and environmental influence on SIN perception. The findings suggest SIN is less heritable than pure tone audiogram (PTA) ability and highly influenced by the environment unique to each twin. Furthermore, a possible role of dietary fat in the etiology of ARHI is highlighted.
Osteoarthritis (OA) is a degenerative joint disease for which there are no disease-modifying drugs. It is a leading cause of disability in the UK. Increasing age and obesity are both major risk factors for OA and the health and economic burden of this disease will increase in the future. Focusing on compounds from the habitual diet that may prevent the onset or slow the progression of OA is a strategy that has been under-investigated to date. An approach that relies on dietary modification is clearly attractive in terms of risk/benefit and more likely to be implementable at the population level. However, before undertaking a full clinical trial to examine potential efficacy, detailed molecular studies are required in order to optimise the design. This review focuses on potential dietary factors that may reduce the risk or progression of OA, including micronutrients, fatty acids, flavonoids and other phytochemicals. It therefore ignores data coming from classical inflammatory arthritides and nutraceuticals such as glucosamine and chondroitin. In conclusion, diet offers a route by which the health of the joint can be protected and OA incidence or progression decreased. In a chronic disease, with risk factors increasing in the population and with no pharmaceutical cure, an understanding of this will be crucial.
Recent acceleration and thinning of Thwaites Glacier, West Antarctica, motivates investigation of the controls upon, and stability of, its present ice-flow pattern. Its eastern shear margin separates Thwaites Glacier from slower-flowing ice and the southern tributaries of Pine Island Glacier. Troughs in Thwaites Glacier’s bed topography bound nearly all of its tributaries, except along this eastern shear margin, which has no clear relationship with regional bed topography along most of its length. Here we use airborne ice-penetrating radar data from the Airborne Geophysical Survey of the Amundsen Sea Embayment, Antarctica (AGASEA) to investigate the nature of the bed across this margin. Radar data reveal slightly higher and rougher bed topography on the slower-flowing side of the margin, along with lower bed reflectivity. However, the change in bed reflectivity across the margin is partially explained by a change in bed roughness. From these observations, we infer that the position of the eastern shear margin is not strongly controlled by local bed topography or other bed properties. Given the potential for future increases in ice flux farther downstream, the eastern shear margin may be vulnerable to migration. However, there is no evidence that this margin is migrating presently, despite ongoing changes farther downstream.
Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
To investigate the subsurface hydrological characteristics of an overdeepened cirque glacier, nine boreholes were drilled to the bed of West Washmawapta Glacier, British Columbia, Canada, in summer 2007. All holes were surveyed with a video camera, and four were subsequently instrumented with a combination of pressure transducers, thermistors and conductivity sensors. Diurnal pressure and temperature records indicate the presence of a hydraulically connected subglacial drainage system towards the northern glacier margin. Hydraulic jacking in the overdeepening, controlled by changing water volume in the marginal zone, potentially impacts basal ice flow and erosion. The presence of a sediment layer underlying the glacier also likely impacts hydrology and ice dynamics. Influx of warm groundwater into the basal system raises subglacial water temperatures above the pressure-melting point (pmp) and induces diurnal water temperature fluctuations of as much as 0.8°C; water temperatures above the pmp could affect basal melt rates and the development of subglacial drainage systems. These observations suggest that the characteristics of the subglacial drainage system substantially affect patterns of flow and erosion by this small cirque glacier.
With a goal toward deriving the physical conditions in external galaxies, we present a survey of formaldehyde (H2CO) and ammonia (NH3) emission and absorption in a sample of starburst galaxies using the Green Bank Telescope. By extending well-established techniques used to derive the spatial density in star formation regions in our own Galaxy, we show how the relative intensity of the 110−111 and 211−212 K-doublet transitions of H2CO can provide an accurate densitometer for the active star formation environments found in starburst galaxies (cf. Mangum et al. 2008). Similarly, we employ the well-established technique of using the relative intensities of the (1,1), (2,2), and (4,4) transitions of NH3 to derive the kinetic temperature in starburst galaxies. Our measurements of the kinetic temperature constrained spatial density in our starburst galaxy sample represent the first mean density measurements made toward starburst galaxies. We note a disparity between kinetic temperature measurements derived assuming direct coupling to dust and those derived from our NH3 measurements which points to the absolute need for direct gas kinetic temperature measurements using an appropriate molecular probe. Finally, our spatial density measurements point to a rough constancy to the spatial density (104.5 to 105.5 cm-3) in our starburst galaxy sample. This implies that the Schmidt-Kennicutt relation between LIR and Mdense: (1) Is a measure of the dense gas mass reservoir available to form stars, and (2) Is not directly dependent upon a higher average density driving the star formation process in the most luminous starburst galaxies.
Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10, 000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10-8) for ND (rs964170 in ARHGAPlOon chromosome 4, p = 4.43 x 10”8) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10-9), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10-9) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10-8)). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepre-sentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be requirec before the detailed causes of comorbidity between AC and ND are understood.
The fertility nurse is an essential member of a multi-professional team whose focus is to ensure the delivery of quality care to patients. Information regarding ovulation induction (OI) and intrauterine insemination (IUI) is introduced to the patient by multiple team members, but most importantly by the nurse. The nurse works with the physicians and other team members, and becomes the primary advocate for the patient.
After the physician designs a plan of treatment based on his or her initial assessment and diagnosis, it is the nurse who coordinates and implements the plan of treatment. During the planning phase, the nurse becomes the primary caregiver and has the majority of interaction with the patient. The nurse's role is to direct couples through their treatment by explaining and defining all procedures and instructions clearly and concisely. It is very important for the nurse to be knowledgeable, compassionate, confident and empathetic.
The nurse implements the physician's plan of treatment by formulating and reviewing the OI patient's cycle calendar, ordering and instructing on the administration of oral or injectable medications, and educating on potential risks and/or side effects. The nurse teaches the patient the purpose of each step in the treatment protocol. The nurse reviews results of ultrasound and labs, and then communicates these results with the physician so as to instruct the patient with her plan of treatment. The nurse has an important role in teaching the patient regarding ovulation predictor kits.
Occasionally the nurse's role includes discussion of costs involved.
Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian samples from Australia (N = 3906) and the Netherlands (N = 1689) for polymorphisms in VDR. The Australian samples were twin families with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height — this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.
To examine the contribution of genetic factors to food choice, we determined dietary patterns from food frequency questionnaires in 3262 UK female twins aged 18 to 79 years. Five distinct dietary patterns were identified (fruit and vegetable, high alcohol, traditional English, dieting, low meat) that accounted for 22% of the total variance. These patterns are similar to those found in other singleton Western populations, and were related to body mass index, smoking status, physical activity and deprivation scores. Older subjects had higher scores on the fruit and vegetable and traditional English patterns, while lower social deprivation was associated with higher scores for fruit and vegetable, and lower scores for traditional English patterns. All 5 patterns were heritable, with estimates ranging from 41% to 48%. Among individual dietary components, a strongly heritable component was identified for garlic (46%), coffee (41%), fruit and vegetable sources (49%), and red meat (39%). Our results indicate that genetic factors have an important influence in determining food choice and dietary habits in Western populations. The relatively high heritability of specific dietary components implicates taste perception as a possible target for future genetic studies.
Linkage analysis (either parametric or nonparametric) is commonly applied to identify chromosomal regions using related individuals affected by disease. In complex disease the incomplete relationship between phenotype and genotype can be modeled using a phenocopy parameter, the probability that an individual is affected given they do not carry the disease mutation of interest, and a nonpenetrance parameter, the probability that an individual is not affected given they do carry the disease mutation of interest. If the linkage phase between multiple markers and a putative disease locus is known, then haplotypes carrying the mutation can, in principle, be identified by comparing the chromosome segments that are shared identical-by-descent (IBD) across affected individuals. We consider here the effect of a nonzero phenocopy rate on the linkage peak and hence upon the identification of disease haplotypes that are shared IBD between affected individuals. We show, by theory and computer simulation, that in diseases for which there is a nonzero phenocopy rate, the chromosomal regions identified may not include the true disease locus. We utilize a LOD-1 confidence interval for a widely used nonparametric linkage statistic. We find that in small/moderate samples this confidence interval may be inappropriate. We give specific examples where the phenocopy rates are nonnegligible in some complex diseases. The success of further work to identify the causal mutations underlying the linkage peaks in these diseases will depend on researchers allowing for the presence of phenocopies by examining appropriately wide regions around the initial positive linkage finding.