Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

Modeling of craton stability using a viscoelastic rheology

Archean cratons belong to the most remarkable features of our planet since they represent continental crust that has avoided reworking for several billions of years. Even more, it has become evident from both geophysical and petrological studies that cratons exhibit deep lithospheric keels which equally remained stable ever since the formation of the cratons in the Archean. Dating of inclusions in diamonds from kimberlite pipes gives Archean ages, suggesting that the Archean lithosphere must have been cold soon after its formation in the Archean (in order to allow for the existence of diamonds) and must have stayed in that state ever since. Yet, although strong evidence for the thermal stability of Archean cratonic lithosphere for billions of years is provided by diamond dating, the long-term thermal stability of cratonic keels was questioned on the basis of numerical modeling results. We devised a viscoelastic mantle convection model for exploring cratonic stability in the stagnant lid regime. Our modeling results indicate that within the limitations of the stagnant lid approach, the application of a sufficiently high temperature-dependent viscosity ratio can provide for thermal craton stability for billions of years. The comparison between simulations with viscous and viscoelastic rheology indicates no significant influence of elasticity on craton stability. Yet, a viscoelastic rheology provides a physical transition from viscously to elastically dominated regimes within the keel, thus rendering introduction of arbitrary viscosity cutoffs, as employed in viscous models, unnecessary

Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma

Published online: 27 July 2018Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide1. Both IOP and POAG are highly heritable2. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)3,4 that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported4-12. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.Stuart MacGregor, Jue-Sheng Ong, Jiyuan An, Xikun Han, Tiger Zhou, Owen M. Siggs, Matthew H. Law, Emmanuelle Souzeau, Shiwani Sharma, David J. Lynn, Jonathan Beesley, Bronwyn Sheldrick, Richard A. Mills, John Landers, Jonathan B. Ruddle, Stuart L. Graham, Paul R. Healey, Andrew J. R. White, Robert J. Casson, Stephen Best, John R Grigg, Ivan Goldberg, Joseph E. Powell, David C. Whiteman, Graham L. Radford-Smith, Nicholas G. Martin, Grant W. Montgomery, Kathryn P. Burdon, David A. Mackey, Puya Gharahkhani, Jamie E. Craig and Alex W. Hewit

A polygenic risk score predicts intraocular pressure readings outside office hours and early morning spikes as measured by home tonometry

OBJECTIVE: Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. DESIGN: Cross-sectional study. PARTICIPANTS: 473 eyes from 239 participants with suspected or established primary open angle glaucoma sampled from the PROGRESSA study from four outpatient ophthalmology clinics in Australia between August 2016 and December 2019. METHODS: Participants underwent Icare HOME tonometer measurements to record IOP four times a day for five days. Unreliable measurements were excluded. A minimum of two days with at least three reliable measurements were required. We used a previously-validated IOP PRS derived from 146 common IOP-associated variants in a linear regression model with adjustment for central corneal thickness and age. MAIN OUTCOME MEASURES: Highest recorded early-morning IOP, and mean IOP within and outside office hours. Early-morning IOP spikers were defined as eyes with a higher early-morning IOP than the highest recorded IOP during office hours. RESULTS: 334 eyes from 176 participants (mean age 64 years, SD 9) generated reliable measurements for inclusion. Eyes in the highest IOP PRS quintile had an early-morning IOP increase by 4.3 mmHg (95% confidence interval [CI] 1.4-7.3; P = 0.005) and mean IOP outside office hours increase of 2.7 mmHg (95% CI 0.61-4.7; P = 0.013) than the lowest quintile, which were independently significant after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to be early-morning IOP spikers than the lowest quintile (odds ratio 95% CI 1.3-23.6; P = 0.023) CONCLUSION: A previously validated IOP PRS was associated with higher early-morning IOP, and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.Ayub Qassim, Sean Mullany, Mona S.Awadalla, Mark M.Hassall, Thi Nguyen, Henry Marshall, Antonia Kolovos, Angela M. Schulz, Xikun Han, Puya Gharahkhani, Anna Galanopoulos, Ashish Agar, Paul R. Healey, Alex W. Hewitt, John Landers, Robert J.Casson, Stuart L.Graham, Stuart MacGregor, Emmanuelle Souzeau, Owen M.Siggs, Jamie E.Crai

Tracking SARS-CoV-2 mutations and variants through the COG-UK-Mutation explorer

COG-UK Mutation Explorer (COG-UK-ME, http://sars2.cvr.gla.ac.uk/cog-uk/-last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics.</p