bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/209270

High genetic loading for schizophrenia predicts poor response to lithium in patients with bipolar disorder: A polygenic score and cross-trait genetic analysis

Amare, A. T.·Schubert, K. O.·The International Consortium on Lithium Genetics,·Schulze, T. G.·Baune, B.
View original source ↗Export metadata ↓

Abstract

ImportanceLithium is a first-line mood stabilizer for the maintenance treatment of Bipolar Disorder (BPD). However, the efficacy of lithium varies widely, with a non-response rate of up to 30%. Biological response markers and predictors are lacking.\n\nObjectiveGenetic factors are thought to mediate lithium treatment response, and the previously reported genetic overlap between BPD and schizophrenia (SCZ) led us to test whether a polygenic score (PGS) for SCZ could predict lithium treatment response in BPD. Further, we explored the potential molecular underpinnings of this association.\n\nDesignWeighted SCZ PGSs were computed at ten p-value thresholds (PT) using summary statistics from a genome-wide association study (GWAS) of 36,989 SCZ cases, and genotype data for BPD patients from the Consortium on Lithium Genetics (ConLi+Gen). For functional exploration, we performed a cross-trait meta-GWAS and pathway analysis, combining GWAS summary statistics on SCZ and lithium treatment response.\n\nSettingInternational multicenter GWAS.\n\nParticipantsPatients with BPD who had undergone lithium treatment were genotyped and retrospectively assessed for long-term treatment response (n=2,586).\n\nMain outcome measuresClinical treatment response to lithium was defined on both the categorical and continuous scales using the ALDA score. The effect measures include odds ratios (ORs) and the proportion of variance explained (R2), and a significant association was determined at p<0.05.\n\nResultsThe PGS for SCZ was inversely associated with lithium treatment response in the categorical outcome (p=8x10-5), at PT <5x10-2. Patients with BPD who had low polygenic load for SCZ responded better to lithium, with ORs for lithium response ranging from 3.46 [95%CI: 1.42-8.41 at 1st decile] to 2.03 [95%CI: 0.86-4.81 at the 9th decile], compared to the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA complex and inflammatory cytokines (TNF, IL-4, IFN{gamma}) as molecular contributors to lithium treatment response in BPD.\n\nConclusions and RelevanceThe study provides, for the first-time, evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDoes a polygenic score for Schizophrenia (SCZ) predict response to lithium in patients with Bipolar Disorder (BPD)? What are the molecular drivers of the association between SCZ and lithium treatment response?\n\nFindingsWe found an inverse association between genetic loading for SCZ risk variants and response to lithium in patients with BPD. Genetic variants in the HLA region on chromosome 6, the antigen presentation pathway and markers of inflammation (TNF, IL-4, IFN{gamma}) point to molecular underpinnings of lithium treatment response in BPD.\n\nMeaningIn patients with BPD, an assessment of a polygenic load for SCZ risk variants may assist in conjunction with clinical data to predict whether they would respond to lithium treatment.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Amare, A. T., Schubert, K. O., The International Consortium on Lithium Genetics,, Schulze, T. G., Baune, B.. 2017-11-11. High genetic loading for schizophrenia predicts poor response to lithium in patients with bipolar disorder: A polygenic score and cross-trait genetic analysis. https://doi.org/10.1101/209270

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

X-Chromosomal STR-based analysis of genetic diversity, structure, and phylogeny in the Sri Lankan Vedda population

The Vedda people are regarded as the direct descendants of Sri Lanka's Mesolithic hunter-gatherers and represent one of South Asia's oldest surviving indigenous populations. X-chromosomal short tandem repeat (X-STR) analysis provides a powerful framework to examine their genetic distinctiveness, as the X chromosome exhibits sex-biased biparental inheritance and greater sensitivity to demographic and evolutionary forces compared to autosomal markers. However, no X-STR-based genetic investigations have yet been conducted on this population. In the present study, we successfully genotyped 50 unrelated Veddas individuals using a recently developed 16 X-STR multiplex PCR system optimized for Sri Lankan populations. Our analyses revealed a statistically significant genetic differentiation (2.43%) between the Veddas and the principal local ethnic groups; Sinhalese, Sri Lankan Tamils, Indian Tamils, and Moors exceeding previous estimates based on autosomal STR markers. Comparative analysis with 32 global populations positioned the Veddas as a genetically distinct and isolated group, separated from clusters representing South Asians, Europeans, Middle Easterners, and other indigenous populations such as Australian Aboriginals, Bhil Indians, and Kedayans, emphasizing their unique genetic heritage. Reduced allelic (115) and haplotype (62) counts, alongside significant linkage disequilibrium detected among eight pairs of X-STR loci, reflect the influence of genetic drift within this small, endogamous, and historically isolated population. These findings highlight the evolutionary and demographic distinctiveness of the Veddas and provide essential baseline data for future population genomic studies. Furthermore, the demonstrated high discriminatory power of the 16 X-STR loci supports their continued application in population genetics and anthropological research within this unique community.

genetics↗
bioRxiv2026

Fss1, a CTNS/PQ domain protein, has dual roles in promoting fertility in Schizosaccharomyces pombe

Sexual reproduction is critical in most eukaryotes, but many genes required for the process remain to be identified and characterized. A previous saturation mutagenesis study in Schizosaccharomyces pombe implicated several unnamed genes in having roles in sexual reproduction. In this work, we provide an initial characterization of 13 of these genes and an in-depth characterization of one gene, fss1 (facilitates starvation sex). Fss1 has high structural homology to the human PQ-loop repeat family PQLC2 transceptor (amino acid transporter plus membrane receptor), but likely lacks the ability to transport amino acids due to loss of a critical PQ motif. fss1{Delta} mutants have no defects in meiosis but have pronounced defects in packaging the products of meiosis into spores, particularly in nutrient-poor environments. The spore formation phenotypes are recessive as fss1{Delta} spores produced by a fss1+/fss1{Delta} heterozygote develop normally. Immuno-gold electron microscopy shows Fss1 localizes to vesicles that fuse to the ephemeral outer spore membrane as the spore wall matures below. Fss1 protein is also produced within spores and this population is required for normal vacuole morphology and timely germination. We propose a model in which Fss1 is a vesicle receptor that facilitates spore wall formation from diploid-expressed protein, while spore-expressed protein acts at the vacuole to promote an internal cellular environment that facilitates germination. This work expands our catalog of genes that contribute to sexual reproduction and identifies two previously unknown tasks in spore biology that are both facilitated by Fss1.

genetics↗
bioRxiv2026

Expression of tardigrade intrinsically disordered proteins in C. elegans reveals variable effects on aging and stress

Tardigrades survive extreme environmental stress by expressing intrinsically disordered proteins that stabilize cellular structures during cryptobiosis. Because these proteins protect cells from desiccation, oxidative stress, and DNA damage, they have attracted interest as potential therapeutics to enhance stress resilience in other organisms. However, most studies have relied on cultured cells or germline expression, leaving their effects in somatic tissues largely unexplored. Here, we generated Caenorhabditis elegans strains expressing four tardigrade intrinsically disordered proteins, Damage Suppressor (DSUP), cytoplasmic-abundant heat-soluble (CAHS), mitochondrial-abundant heat-soluble (MAHS), and Ramazzottius varieornatus late embryogenesis abundant (RvLEAM), throughout somatic tissues. Surprisingly, constitutive expression of each protein reduced lifespan, impaired motility and reproduction, and failed to improve resistance to most environmental stressors. DSUP toxicity was tissue- and developmental stage-dependent, indicating that both spatial and temporal expression influence its physiological effects. Despite these detrimental phenotypes, several proteins reduced protein aggregation during desiccation-associated stress, demonstrating context-dependent protective effects. Together, our findings reveal that tardigrade stress proteins impose physiological tradeoffs in vivo and underscore the importance of evaluating candidate stress-protective proteins in physiologically relevant somatic models before therapeutic translation.

genetics↗