Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants

Genetic analysis of neuropsychiatric disorders in a South American population isolate.

Bipolar disorder (BP) and schizophrenia are severe neuropsychiatric conditions that are among the leading causes of morbidity and chronic disability world-wide. Both conditions are characterised by a substantial genetic heterogeneity, which has complicated the search for susceptibility loci. One strategy to tackle this difficulty lies in the study of population isolates that are characterised by a reduced genetic heterogeneity. In this thesis, I have therefore conducted genetic studies of BP and schizophrenia in the well-characterised South American population isolate of Antioquia, Colombia. Our group has recently reported the results of a linkage scan of six Antioquian families segregating severe BP. Here, I performed a follow-up study of a candidate region on chromosome 5q33. I sequenced the CLINT 1 gene, a functional candidate that has also been implicated in schizophrenia, in affecteds from four BP pedigrees from the original linkage study and identified three single base pair variants, all of which had been previously described. A transmission distortion test of one of these variants, rs 11955293, in a sample of 176 unrelated BP patients from Antioquia and their parents found no evidence of association with BP. Although these results do not rule out a minor effect of the CLINT1 gene on susceptibility to the disorder in Antioquia, other loci are likely to be of greater significance. This includes other genes on chromosome 5q33, but also other candidate regions in the genome. To further explore the latter possibility, I conducted a whole-genome linkage scan in an additional nine pedigrees with severe BP from Antioquia and analysed the obtained genotype data jointly with that of the initial linkage scan. Using parametric and non-parametric linkage approaches, I explored three different diagnostic models: a narrow model including only BP type I (BPI) as affected a model including BPI and II and major unipolar depression and a third model including only individuals who had experienced psychosis as affected. This second linkage scan found evidence for a number of candidate regions, including chromosome 13q33 for BPI, chromosomes lpl3-31 and lq25-31 for mood disorders, chromosome 12ct-ql4 for mood disorders, and chromosomes 2q24-31 and 16pl2 for psychosis. Encouragingly, many of these loci had previously been pinpointed as BP susceptibility loci in other populations on the other hand, we also identified a novel locus on chromosome 12q. While the use of population isolates can help decrease the genetic heterogeneity of a complex disease, complementary strategies can be used to reduce this heterogeneity even further. In studying the NOS1AP gene, a functional candidate on chromosome lq23 that is involved in glutamatergic neurotransmission, in a sample of 102 unrelated Antioquian schizophrenia patients and their parents, I have therefore used both categorical and dimensional approaches to the disease phenotype. In the categorical approach, I conducted an analysis for association between the NOS1AP gene and DSM-IV schizophrenia by TDT. For the dimensional approach, two clinical scales measuring positive and negative symptoms, SANS and SAPS, were applied to all patients and dimensional scores were obtained from these scales by factors analysis. I then performed quantitative TDT analysis of the dimensional scores. My analyses found association to both DSM-IV schizophrenia and a clinical dimension capturing negative symptoms, in line with a role of NOS1AP in glutamatergic neurotransmission. The results of these analyses also underline the usefulness of a dimensional approach in psychiatric genetics

Ultrafast Electron Diffuse Scattering as a Tool for Studying Phonon Transport: Phonon Hydrodynamics and Second Sound Oscillations

Hydrodynamic phonon transport phenomena, like second sound, have been observed in liquid Helium temperatures more than 50 years ago. More recently second sound has been observed in graphite at over 200\,K using transient thermal grating techniques. In this work we explore the signatures of second sound in ultrafast electron diffuse scattering (UEDS) patterns. We use density functional theory and solve the Boltzmann transport equation to determine time-resolved non-equilibrium phonon populations and subsequently calculate one-phonon structure factors and diffuse scattering patterns to simulate experimental data covering the regimes of ballistic, diffusive, and hydrodynamic phonon transport. For systems like graphite, UEDS is capable of extracting time-dependent phonon occupancies across the entire Brillouin zone and ultimately lead to a more fundamental understanding of the hydrodynamic phonon transport regime.Comment: 7 pages, 4 figure

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.Peer reviewe

Genome-wide association study of Tourette Syndrome

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses

Overview over the neutral gas pressures in Wendelstein 7-X during divertor operation under boronized wall conditions

During the first test divertor campaign of the stellarator experiment Wendelstein 7-X (Pedersen et al 2022 Nucl. Fusion 62 042022), OP1.2b, 13 neutral gas pressure gauges collected data in different locations in the plasma vessel, enabling a detailed analysis of the neutral gas pressures, the compression ratios and the particle exhaust rates via the turbomolecular pumps in the different magnetic field configurations. In Wendelstein 7-X, the edge magnetic islands are intersected by the divertor target plates and used to create a plasma-wall interface. As the number and position of the magnetic islands varies in different magnetic field configurations, the position of the strike line on the target plates and thus the neutral gas pressure in the subdivertor differs between the configurations. Neutral gas pressures on the order of few 10−4 mbar were measured in the subdivertor region. The highest neutral gas pressure of $1.75\times 10^{-3}$ mbar was obtained in the so-called high iota configuration featuring four edge magnetic islands per cross section. The neutral particle flux through the pumping gaps into the subdivertor volume was provided by EMC3-EIRENE simulations and allowed to analyze the relation between the particle flux entering the subdivertor and the pressure distribution in the subdivertor. Finite element simulations in ANSYS provide a detailed picture of the pressure distribution in the subdivertor volume and agree with the neutral gas pressure measurements in the subdivertor in the standard configuration featuring an island chain of 5 edge magnetic islands. Surprisingly high neutral gas pressures that were not predicted by the simulation were measured in the subdivertor region away from the main strike line for discharges in the most used magnetic configuration, the standard configuration. While the pressure ratio between the two sections of the subdivertor volume, the low and high iota section is 0.06 in high iota configuration, a ratio of 2–5 was obtained in the other configurations, indicating significant particle loads and exhaust rates on the high iota section of the subdivertor in magnetic configurations with the main strike line on the low iota divertor targets