The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

Isolation, Derivative Synthesis, and Structure–Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge <i>Tedania brasiliensis</i>

The isolation and identification of a series of new pseudoceratidine (<b>1</b>) derivatives from the sponge <i>Tedania brasiliensis</i> enabled the evaluation of their antiparasitic activity against <i>Plasmodium falciparum</i>, <i>Leishmania (Leishmania) amazonensis</i>, <i>Leishmania</i> (<i>Leishmania</i>) <i>infantum</i>, and <i>Trypanosoma cruzi</i>, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (<b>4</b>), 20-debromopseudoceratidine (<b>5</b>), 4-bromopseudoceratidine (<b>6</b>), 19-bromopseudoceratidine (<b>7</b>), and 4,19-dibromopseudoceratidine (<b>8</b>) are reported. New tedamides A–D (<b>9</b>–<b>12</b>), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1<i>H</i>-pyrrole-2-carboxamide moiety, are also described. Compounds <b>4</b> and <b>5</b>, <b>6</b> and <b>7</b>, <b>9</b> and <b>10</b>, and <b>11</b> and <b>12</b> have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides <b>9</b>+<b>10</b> and <b>11</b>+<b>12</b> were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. <i>N</i>¹²-Acetylpseudoceratidine (<b>2</b>) and <i>N</i>¹²-formylpseudoceratidine (<b>3</b>) were obtained by derivatization of pseudoceratidine (<b>1</b>). The antiparasitic activity of pseudoceratidine (<b>1</b>) led us to synthesize 23 derivatives (<b>16</b>, <b>17</b>, <b>20</b>, <b>21</b>, <b>23</b>, <b>25</b>, <b>27</b>–<b>29</b>, <b>31</b>, <b>33</b>, <b>35</b>, <b>38</b>, <b>39</b>, <b>42</b>, <b>43</b>, <b>46</b>, <b>47</b>, <b>50</b>, and <b>51</b>) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (<b>1</b>) and derivatives <b>4</b>, <b>5</b>, <b>16</b>, <b>23</b>, <b>25</b>, <b>31</b>, and <b>50</b> provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against <i>Leishmania</i> amastigotes and against <i>P. falciparum</i>. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs