Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.
In a preceding paper 1 we reported on a systematic study of potentiometric responses to neutral phenols (ArOH) by poly(vinyl chloride) (PVC) matrix liquid membranes based on quaternary ammonium or phosphonium salts (Q + X -), and proposed a new model for the observed anionic responses. In this model, the decrease in the amount of Q + and X -that are chargeseparated across the membrane interface is explained on the basis of the following two processes: (i) Complexation of Q + X -and the extracted ArOH, leading to a net movement of anionic species (X -) from the aqueous to the membrane phase. (ii) Proton dissociation of the complexed ArOH and concomitant ejection of HX into the aqueous phase, involving a net movement of cationic species (H + ) from the membrane to the aqueous phase. A theoretical treatment based on the above model reproduced the potentiometric response behaviors for undissociated phenols. This model was further supported by optical second harmonic generation (SHG), which enabled a direct observation of the processes occurring at the interface of a liquid membrane and an aqueous solution.Based on the findings of Kimura et al.2 that a macrocyclic polyamine forms complexes with neutral phenols in aqueous solutions, we previously examined potentiometric responses to phenols by a PVC matrix liquid membrane based on lipophilic macrocyclic pentaamine 1, and found that the membrane exhibits anionic responses to undissociated, neutral phenols.3,4 This response behavior is quite similar to that observed for PVC matrix liquid membranes based on quaternary ammonium or phosphonium salts. A variety of lipophilic amines incorporated in PVC matrix liquid membranes exhibited anionic potentiometric responses to phenolic compounds at the pH conditions under which the phenols exist mainly or exclusively in their undissociated, neutral forms. The examined lipophilic amines include a macrocyclic pentaamine, tri(decyl)amine, 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline), 4-octadecylpyridine, and sapphyrin. The potentiometric selectivities of the membranes based on lipophilic aliphatic amines (B) reflected the acidity (hydrogen bond donor activity) and lipophilicity (extractability) of the phenols (ArOH), similarly as membranes based on lipophilic quaternary ammonium salts (Q + X -). The anionic responses were explained on the basis of a decrease in the charge separation of protonated amines (BH + ) and their counteranions (X -) across the membrane interface. Possible processes leading to a decrease in the charge separation between BH + and X -are (i) complexation between ArOH and BH + X -, followed by proton dissociation and ejection of HX into the aqueous phase, as well as (ii) complexation between ArOH and B. The membrane based on sapphyrin showed a high potentiometric selectivity to catechol, possibly due to geometrical discrimination of the ortho dihydroxy structure of catechol by the nitrogen(s) on the rigid macrocyclic structure of sapphyrin.
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