Tobet, S. | bioRxiv Science

bioRxiv2026

Subcellular partitioning of Nhlh2 mRNA reveals how SNORD116 loss contributes to Prader-Willi Syndrome.

Deletion of the SNORD116 non-coding RNA is associated with the development of Prader-Willi Syndrome (PWS). We and others have identified NHLH2/Nhlh2 as a putative SNORD116/Snord116 target and in this study report that Nhlh2 and Snord116 are co-expressed in forebrain neurons. Nhlh2 mRNA is found predominantly in the nucleus of Snord116+ hypothalamic neurons but is evenly distributed between the nuclear and cytoplasmic compartments in Snord116- neurons. A hypothalamic cell line co-expressing Nhlh2 and Snord116 recapitulates this nuclear partitioning pattern for Nhlh2 only when the putative Snord116 binding site is present in the 3 untranslated region of the Nhlh2 mRNA. In a PWS mouse model (Snord116del), Nhlh2 mRNA levels are unchanged in Pomc neurons but are reduced and primarily cytoplasmic in lateral hypothalamic neurons. These findings demonstrate that Snord116 regulates mRNA levels via mRNA partitioning, fundamentally altering our understanding of gene expression networks in PWS. HighlightsO_LISnord116 snoRNA and its mRNA target Nhlh2 are co-expressed in forebrain neurons. C_LIO_LINhlh2 mRNA is predominantly nuclear co-localized in hypothalamic Snord116+ neurons. C_LIO_LIA putative Snord116 binding site is within the region required for cellular partitioning. C_LIO_LINhlh2 partitioning is lost in Snord116del mice, a model of Prader-Willi Syndrome. C_LI

neuroscience↗

bioRxiv2020

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODSWe conducted the largest to date genome-wide genotype-by-sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

genetics↗