Molecular genetics of bipolar disorder

Bipolar affective disorder has a strong genetic heritability. In the UCL laboratory, a locus on chromosome 1p36 was found to be linked to bipolar and related unipolar affective disorders with a log of the odds score above 3.00. This region was subjected to fine mapping using tests of allelic association in a case-control sample as part of this thesis in order to identify the genes involved in bipolar disorder. In addition, a GWAS was also employed to fine map other bipolar affective disorder susceptibility genes. The tests of allelic association found evidence for the involvement of the PRKCZ gene. Markers D1S243 and rs3128396 at the PRKCZ gene were significantly associated with bipolar disorder with empirical P = 0.037 and P = 0.040, respectively. Other loci encoding brain expressed proteins found to be associated in the UCL GWAS sample were the genes - GRM3 and GRM7. Therefore, these genes were sequenced using PCR-based genomic sequencing. A 3'-UTR base pair change (rs56173829) in the GRM7 gene was found to be significantly associated with the disorder, although the minor allele was more frequent in controls. A base pair mutation (rs148754219) was found in the GRM3 exon 1 two bases before the translation start codon (forming part of Kozak sequence) of a GRM3 receptor isoform. The mutation was associated with bipolar disorder (P = 0.0046, odds ratio 4.2 (95% CI 1.42-12.37). Transcription factor binding assays and cloning experiments comparing the gene expression activity of wild-type and mutant alleles showed that the mutant allele strongly affected the reporter gene activity in SH-SY5Y and HEK293 cells. If the GRM3 Kozak sequence mutation is confirmed as an important mutation in the aetiology of bipolar disorder, then it could be used as a marker for personalised treatment for a genetic subtype of affective disorders

Weighing neutrinos using high redshift galaxy luminosity functions

Laboratory experiments measuring neutrino oscillations, indicate small mass differences between different mass eigenstates of neutrinos. The absolute mass scale is however not determined, with at present the strongest upper limits coming from astronomical observations rather than terrestrial experiments. The presence of massive neutrinos suppresses the growth of perturbations below a characteristic mass scale, thereby leading to a decreased abundance of collapsed dark matter halos. Here we show that this effect can significantly alter the predicted luminosity function (LF) of high redshift galaxies. In particular we demonstrate that a stringent constraint on the neutrino mass can be obtained using the well measured galaxy LF and our semi-analytic structure formation models. Combining the constraints from the Wilkinson Microwave Anisotropy Probe 7 year (WMAP7) data with the LF data at z = 4, we get a limit on the sum of the masses of 3 degenerate neutrinos \Sigma m_\nu < 0.52 eV at the 95 % CL. The additional constraints using the prior on Hubble constant strengthens this limit to \Sigma m_\nu < 0.29 eV at the 95 % CL. This neutrino mass limit is a factor of order 4 improvement compared to the constraint based on the WMAP7 data alone, and as stringent as known limits based on other astronomical observations. As different astronomical measurements may suffer from different set of biases, the method presented here provides a complementary probe of \Sigma m_\nu . We suggest that repeating this exercise on well measured luminosity functions over different redshift ranges can provide independent and tighter constraints on \Sigma m_\nu .Comment: 14 pages, 7 figures, submitted to PR

Primordial Magnetic Field Limits from Cosmic Microwave Background Bispectrum of Magnetic Passive Scalar Modes

Primordial magnetic fields lead to non-Gaussian signals in the cosmic microwave background (CMB) even at the lowest order, as magnetic stresses and the temperature anisotropy they induce depend quadratically on the magnetic field. In contrast, CMB non-Gaussianity due to inflationary scalar perturbations arises only as a higher order effect. Apart from a compensated scalar mode, stochastic primordial magnetic fields also produce scalar anisotropic stress that remains uncompensated till neutrino decoupling. This gives rise to an adiabatic-like scalar perturbation mode that evolves passively thereafter (called the passive mode). We compute the CMB reduced bispectrum ($b_{l_{_1}l_{_2}l_{_3}}$) induced by this passive mode, sourced via the Sachs-Wolfe effect, on large angular scales. For any configuration of bispectrum, taking a partial sum over mode-coupling terms, we find a typical value of $l_1(l_1+1)l_3(l_3+1) b_{l_{_1}l_{_2}l_{_3}} \sim 6-9 \times 10^{-16}$, for a magnetic field of $B_0 \sim 3$ nG, assuming a nearly scale-invariant magnetic spectrum . We also evaluate, in full, the bispectrum for the squeezed collinear configuration over all angular mode-coupling terms and find $l_1(l_1+1)l_3(l_3+1) b_{l_{_1}l_{_2}l_{_3}} \approx -1.4 \times 10^{-16}$. These values are more than $\sim 10^6$ times larger than the previously calculated magnetic compensated scalar mode CMB bispectrum. Observational limits on the bispectrum from WMAP7 data allow us to set upper limits of $B_0 \sim 2$ nG on the present value of the cosmic magnetic field of primordial origin. This is over 10 times more stringent than earlier limits on $B_0$ based on the compensated mode bispectrum.Comment: 9 page

A Unified treatment of small and large- scale dynamos in helical turbulence

Helical turbulence is thought to provide the key to the generation of large-scale magnetic fields. Turbulence also generically leads to rapidly growing small-scale magnetic fields correlated on the turbulence scales. These two processes are usually studied separately. We give here a unified treatment of both processes, in the case of random fields, incorporating also a simple model non-linear drift. In the process we uncover an interesting plausible saturated state of the small-scale dynamo and a novel analogy between quantum mechanical (QM) tunneling and the generation of large scale fields. The steady state problem of the combined small/large scale dynamo, is mapped to a zero-energy, QM potential problem; but a potential which, for non-zero mean helicity, allows tunneling of bound states. A field generated by the small-scale dynamo, can 'tunnel' to produce large-scale correlations, which in steady state, correspond to a force-free 'mean' field.Comment: 4 pages, 1 figure, Physical Review Letters, in pres

Constrained semi-analytical models of Galactic outflows

We present semi-analytic models of galactic outflows, constrained by available observations on high redshift star formation and reionization. Galactic outflows are modeled in a manner akin to models of stellar wind blown bubbles. Large scale outflows can generically escape from low mass halos (M<10^9 M_sun) for a wide range of model parameters but not from high mass halos (M> 10^{11} M_sun). The gas phase metallicity of the outflow and within the galaxy are computed. Ionization states of different metal species are calculated and used to examine the detectability of metal lines from the outflows. The global influence of galactic outflows is also investigated. Models with only atomic cooled halos significantly fill the IGM at z~3 with metals (with -2.5>[Z/Z_sun]>-3.7), the actual extent depending on the efficiency of winds, the IMF, the fractional mass that goes through star formation and the reionization history of the universe. In these models, a large fraction of outflows at z~3 are supersonic, hot (T> 10^5 K) and have low density, making metal lines difficult to detect. They may also result in significant perturbations in the IGM gas on scales probed by the Lyman-alpha forest. On the contrary, models including molecular cooled halos with a normal mode of star formation can potentially volume fill the universe at z> 8 without drastic dynamic effects on the IGM, thereby setting up a possible metallicity floor (-4.0<[Z/Z_sun]<-3.6). Interestingly, molecular cooled halos with a ``top-heavy'' mode of star formation are not very successful in establishing the metallicity floor because of the additional radiative feedback, that they induce. (Abridged)Comment: 27 pages, 31 figures, 2 tables, pdflatex. Accepted for publication in MNRA

Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder

Background: Bipolar affective disorder (BPD) is a severe mood disorder with a prevalence of ∼ 1.5% in the population. The pathogenesis of BPD is poorly understood; however, a strong heritable component has been identified. Previous genome-wide association studies have indicated a region on 6q25, coding for the SYNE1 gene, which increases disease susceptibility. SYNE1 encodes the synaptic nuclear envelope protein-1, nesprin-1. A brain-specific splice variant of SYNE1, CPG2 encoding candidate plasticity gene 2, has been identified. The intronic single-nucleotide polymorphism with the strongest genome-wide significant association in BPD, rs9371601, is present in both SYNE1 and CPG2. / Methods: We screened 937 BPD samples for genetic variation in SYNE1 exons 14–33, which covers the CPG2 region, using high-resolution melt analysis. In addition, we screened two regions of increased transcriptional activity, one of them proposed to be the CPG2 promoter region. / Results and Conclusion: We identified six nonsynonymous and six synonymous variants. We genotyped three rare nonsynonymous variants, rs374866393, rs148346599 and rs200629713, in a total of 1099 BPD samples and 1056 controls. Burden analysis of these rare variants did not show a significant association with BPD. However, nine patients are compound heterozygotes for variants in SYNE1/CPG2, suggesting that rare coding variants may contribute significantly towards the complex genetic architecture underlying BPD. Imputation analysis in our own wholegenome sequencing sample of 99 BPD individuals identified an additional eight risk variants in the CPG2 region of SYNE1