Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Learning new sensorimotor contingencies:Effects of long-term use of sensory augmentation on the brain and conscious perception

Theories of embodied cognition propose that perception is shaped by sensory stimuli and by the actions of the organism. Following sensorimotor contingency theory, the mastery of lawful relations between own behavior and resulting changes in sensory signals, called sensorimotor contingencies, is constitutive of conscious perception. Sensorimotor contingency theory predicts that, after training, knowledge relating to new sensorimotor contingencies develops, leading to changes in the activation of sensorimotor systems, and concomitant changes in perception. In the present study, we spell out this hypothesis in detail and investigate whether it is possible to learn new sensorimotor contingencies by sensory augmentation. Specifically, we designed an fMRI compatible sensory augmentation device, the feelSpace belt, which gives orientation information about the direction of magnetic north via vibrotactile stimulation on the waist of participants. In a longitudinal study, participants trained with this belt for seven weeks in natural environment. Our EEG results indicate that training with the belt leads to changes in sleep architecture early in the training phase, compatible with the consolidation of procedural learning as well as increased sensorimotor processing and motor programming. The fMRI results suggest that training entails activity in sensory as well as higher motor centers and brain areas known to be involved in navigation. These neural changes are accompanied with changes in how space and the belt signal are perceived, as well as with increased trust in navigational ability. Thus, our data on physiological processes and subjective experiences are compatible with the hypothesis that new sensorimotor contingencies can be acquired using sensory augmentation

Distributions of branched GDGTs in soils and lake sediments from western Uganda: Implications for a lacustrine paleothermometer

Bacterially produced branched glycerol dialkyl glycerol tetraethers (GDGTs) are ubiquitous in soils and lake sediments and can potentially be used to reconstruct past temperatures. In lakes, however, it is still unclear if these compounds are derived from eroded soils or if they are produced in situ. To better understand environmental controls on the distributions of these compounds and the sources of branched GDGTs to lake sediments, we compare branched GDGT distributions and concentrations in lake sediments and catchment soils within a 3600 m altitudinal transect in western Uganda. Reconstructed mean annual air temperature (MAAT), determined from the degree of methylation (MBT) and cyclisation (CBT) of branched GDGTs in soils, decreases with increasing altitude, as is expected from the air temperature gradient in our transect. However, we observe significant offsets between observed and reconstructed temperatures in soils from wet, high elevation soils but not in most dry, low elevation soils. Branched GDGT distributions differ significantly between lake sediments and soils at all elevations, with greater differences at low elevations than at high elevations. These data support previous hypotheses that branched GDGTs are produced in situ in lakes and suggest that the abundance of water in soil environments may play a role in controlling the distribution of branched GDGTs. While branched GDGTs in lacustrine sediments can be used to reconstruct temporal temperature variations in lakes, we urge caution in utilizing this proxy in lacustrine systems with high soil loadings, especially if there is evidence of changing clastic fluxes through time

Seasonal variability of branched glycerol dialkyl glycerol tetraethers (brGDGTs) in a temperate lake system

Quantitative climate reconstructions are crucial for understanding the magnitude of and mechanisms behind natural and anthropogenic climate change, yet there are few proxies that can reliably reconstruct terrestrial temperature. Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are bacterial membrane lipids that are increasingly used to reconstruct paleotemperature from lake sediments, but despite their potential, we have a poor understanding of (1) autochthonous vs. allochthonous sources of brGDGTs in lakes and (2) the seasonality of and environmental controls on brGDGT production within lakes. To investigate these factors, we examined water column suspended particulate matter (SPM) and settling particles from a sediment trap collected on a biweekly to monthly basis over a period of three years at Lower King Pond, a small kettle lake in northern Vermont, USA. We also compared the concentration and fractional abundances of brGDGTs in SPM and settling particles with those of catchment soils, river sediments, and lake surface sediments to constrain the relative importance of brGDGTs derived from the landscape versus brGDGTs produced within the lake itself. We find significant differences in concentrations and fractional abundances of brGDGTs between soil and river sediment samples from the catchment and lake sediments, indicating a mostly autochthonous source for lacustrine brGDGTs. BrGDGT concentrations, fluxes, and fractional abundances in SPM vary over the annual cycle, indicating that brGDGTs are produced throughout the year and respond to changes within the water column. The total annual flux of brGDGTs settling through the water column is comparable to the brGDGT accumulation rates in surface sediments, indicating that in this lake brGDGTs are mostly produced within the water column, not in the sediment itself. While brGDGTs are produced in all seasons within the water column, the flux to the sediments is highest during periods of spring and fall isothermal mixing, potentially biasing paleotemperature reconstructions towards mixing season temperature. Because the seasonal timing and frequency of lake mixing varies as a function of regional climate, lacustrine brGDGT calibrations should be regional in nature and comprise lakes with similar mixing regimes

Effects of temperature, pH and nutrient concentration on branched GDGT distributions in East African lakes: Implications for paleoenvironmental reconstruction

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are membrane lipids found in soils and sediments and their relative abundance correlates with temperature and pH, enabling them to be used as proxies in reconstructing past climatic and environmental conditions. However, the potential for other environmental variables, such as nutrient concentration, to affect brGDGT distributions remains largely unexplored. We have examined the influence of a suite of environmental factors, including temperature, lake water and sediment chemistry, and lake morphometry on brGDGT concentration and distributions in the surface sediments of 111 lakes in East Africa. We found that temperature was the major control on the distributions, while the influence of pH was relatively minor. Water depth also had a minor but statistically significant influence, perhaps due to the relationship between lake depth and deep water anoxia. Water column nutrient concentration did not have a significant effect on the distributions or concentration. We further explored the potential for these variables to affect brGDGT temperature reconstruction by examining the correlation between them and the residuals of our brGDGT temperature calibration. We found that, while the distribution of some cyclized brGDGTs may be influenced by pH and other environmental variables, they are necessary in brGDGT calibration equations in order to accurately reconstruct temperature, likely due to covariation between temperature and other environmental variables. While surface water pH correlated with the relative abundance of certain brGDGTs, caution should be exhibited when using brGDGTs as a pH proxy because of systematic calibration errors

Distributions of 5- and 6-methyl branched glycerol dialkyl glycerol tetraethers (brGDGTs) in East African lake sediment: Effects of temperature, pH, and new lacustrine paleotemperature calibrations

The distribution of branched glycerol dialkyl glycerol tetraethers (brGDGTs) in soils, peats, and lake sedimentshas been shown to correlate with mean annual air temperature (MAAT) and has provided valuablenew climate reconstructions. Here we use an improved chromatographic method to quantify the fractionalabundances of 5- and 6-methyl isomers in surface sediments from 65 East African lakes spanningtemperatures 1.6–26.8 °C, and investigate the relationships between these fractional abundances andtemperature, lake pH, and other environmental variables. We find that temperature exerts a strong controlon brGDGT distributions, including the relative abundances of 5- and 6-methyl isomers, whereasother environmental variables, including lake pH, are weakly correlated to the fractional abundancesof the brGDGTs. The distributions of brGDGTs in our lake sediments differ from those of soils and peats,leading to temperature offsets if soil- and peat-based brGDGT temperature calibrations are applied. Wedevelop new calibrations for MAAT for use in lake sediment based upon the MBT05Me and Index 1 ratios,as well as a multivariate regression of brGDGT fractional abundances on temperature using stepwiseforward selection. We obtain root mean square errors (RMSE) between ? 2.1 and 2.5 °C for these calibrations,highlighting the potential for brGDGTs to provide precise temperature reconstructions using lakesediment cores. Calibrations for lake pH perform more poorly, likely due to weak correlations betweenpH and brGDGT distributions in East African lakes. These results indicate that quantification of 5- and6-methyl isomers separately in lake sediment can improve paleoclimatic reconstructions

Calibration and application of the branched GDGT proxy on East African lake sediments

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are a novel proxy for mean annual air temperature (MAAT) and have the potential to be broadly applicable to climate reconstruction using lacustrine sediments. Several calibrations have been put forth relating brGDGT distributions to MAAT using a variety of linear regressions, including the methylation (MBT) and cyclization (CBT) indices of brGDGTs, the relative abundances of the major, non-cyclized brGDGTs (MbrGDGTs), and best subsets regression (BSR) of the fractional abundances of the nine most common brGDGTs. However, these calibrations have rarely been applied to lake sediment cores to reconstruct temperatures and test the applicability of this proxy as a paleothermometer. We present an expanded East African lakes surface sediment brGDGT dataset based upon 111 lakes and examine three methods of calibrating brGDGTs to MAAT. These methods include recalculations of the East African lake MBT/CBT calibration and MbrGDGTs calibrations, as well as a new stepwise forward selection (SFS) calibration that uses the four combined brGDGTs that explain the most variance in temperature in our calibration set. We apply these new calibrations as well as five previously published lacustrine brGDGT calibrations to the brGDGT distributions of our surface sediment dataset and a 48 kyr sediment core from Sacred Lake, Mt. Kenya, producing the first brGDGT temperature reconstruction available from a small tropical lake. We compare the reconstructed temperatures to previously published paleotemperature records from East Africa to help us assess the performance of the brGDGT calibrations. We find that the SFS calibration has a consistently low root mean squared error of prediction (RMSEP) over the entire range of MAAT, while the MBT/CBT and MbrGDGT calibrations have relatively large RMSEPs, particularly between lakes with similar temperatures but variable pH. This suggests that these techniques do not properly deconvolve the temperature and pH signals recorded in the distributions of the brGDGTs. We further find that only the SFS calibration produces a credible reconstructed temperature history from Sacred Lake when compared to other last glacial maximum paleotemperature estimates from East Africa. Thus, we advocate for the use of the SFS calibration when reconstructing paleotemperatures from brGDGTs in East Africa

Calibration and application of the branched GDGT proxy on East African lake sediments

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are a novel proxy for mean annual air temperature (MAAT) and have the potential to be broadly applicable to climate reconstruction using lacustrine sediments. Several calibrations have been put forth relating brGDGT distributions to MAAT using a variety of linear regressions, including the methylation (MBT) and cyclization (CBT) indices of brGDGTs, the relative abundances of the major, non-cyclized brGDGTs (MbrGDGTs), and best subsets regression (BSR) of the fractional abundances of the nine most common brGDGTs. However, these calibrations have rarely been applied to lake sediment cores to reconstruct temperatures and test the applicability of this proxy as a paleothermometer. We present an expanded East African lakes surface sediment brGDGT dataset based upon 111 lakes and examine three methods of calibrating brGDGTs to MAAT. These methods include recalculations of the East African lake MBT/CBT calibration and MbrGDGTs calibrations, as well as a new stepwise forward selection (SFS) calibration that uses the four combined brGDGTs that explain the most variance in temperature in our calibration set. We apply these new calibrations as well as five previously published lacustrine brGDGT calibrations to the brGDGT distributions of our surface sediment dataset and a 48 kyr sediment core from Sacred Lake, Mt. Kenya, producing the first brGDGT temperature reconstruction available from a small tropical lake. We compare the reconstructed temperatures to previously published paleotemperature records from East Africa to help us assess the performance of the brGDGT calibrations. We find that the SFS calibration has a consistently low root mean squared error of prediction (RMSEP) over the entire range of MAAT, while the MBT/CBT and MbrGDGT calibrations have relatively large RMSEPs, particularly between lakes with similar temperatures but variable pH. This suggests that these techniques do not properly deconvolve the temperature and pH signals recorded in the distributions of the brGDGTs. We further find that only the SFS calibration produces a credible reconstructed temperature history from Sacred Lake when compared to other last glacial maximum paleotemperature estimates from East Africa. Thus, we advocate for the use of the SFS calibration when reconstructing paleotemperatures from brGDGTs in East Africa