Biology subjects

Peterson, R.

Publications and source records attributed to Peterson, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Microbiome-mediated Biotransformation of Human Lactoferrin (effera(R)) Enhances Epithelial Barrier Function in an Ex Vivo Adult Model

Lactoferrin is a multifunctional iron-binding glycoprotein that supports intestinal barrier function, immune regulation, and a favorable gut microbial environment. However, the contribution of gut microbial biotransformation to its gastrointestinal activity remains poorly understood. We investigated whether effera(R), a precision fermentation-derived recombinant human lactoferrin, supports intestinal barrier function through microbiome-mediated mechanisms. effera(R) underwent simulated upper gastrointestinal digestion followed by ex vivo colonic fermentation using the validated SIFR(R) technology pipeline, which employs bioreactors that are inoculated with fecal microbiota from six healthy adult donors. Microbial activity was evaluated by measuring short-chain fatty acid (SCFA) production, bacterial cell density, and microbiome composition. effera(R) produced dose-dependent increases in the production of SCFAs and bacterial cell density demonstrating enhanced microbial metabolic activity. These metabolic changes were accompanied by shifts in key microbial groups within Bacillota_A and Bacteroidota. Intact effera(R) and cell-free post-colonic fermentation-derived products were evaluated in a Caco-2/THP-1 epithelial-immune co-culture model under basal and lipopolysaccharide-challenged conditions. Whereas intact protein did not significantly improve epithelial barrier integrity, effera(R)s post-colonic fermentation-derived products significantly enhanced transepithelial electrical resistance (TEER) under basal conditions and produced an even stronger barrier-protective response following LPS challenge. Across matched doses, effera(R) consistently generated greater TEER responses than bovine lactoferrin. Improved barrier function was accompanied by increased expression of tight-junction-associated targets ZO-1 and occludin and reduced secretion of CXCL-10 and IL-8. Together, these findings demonstrate that microbial biotransformation enhances the biological activity of effera(R), linking increased microbial metabolism with improved epithelial barrier integrity and modulation of inflammatory signaling. This integrated study provides a strong mechanistic foundation for the use of human lactoferrin in adult gut-health applications and offers valuable guidance for future adult clinical studies and infant-relevant investigations.

microbiology↗

bioRxiv2026

A dCas9 Proximity Reporter for Investigating DNA Linear and Rotational Dynamics

The dCas9 system has rapidly been developed into many tools to explore different aspects of the human genome; the high binding specificity, coupled with the inactive nuclease enzyme, allows for precise recruitment of molecules to specific sequences of DNA. We sought to exploit these capabilities to create a tool for assessing the real-time proximity of two DNA sequences within a biological system. By incorporating aptamers into gRNAs, dCas9 molecules can be used to recruit the {beta}9 or {beta}10 strands of split-NanoLuc(R) to specific DNA sequences and quantify the proximity of those sequences based on their ability to complex with the luciferase fragment ({Delta}11S) and produce luminescence. While many tools exist to detect a single DNA sequence, this system is uniquely capable of assessing how two DNA sequences interact with each other. As expected, we found that the interaction of two dCas9 molecules was affected by their linear distance from each other on dsDNA. Surprisingly, we found that their interaction was also strongly influenced by rotational orientation, even for sequences that are close together in linear space. This finding indicates that dCas9 rotational alignment is an important consideration for designing dCas9 systems that target multiple DNA sequences simultaneously. Beyond the findings presented herein, we believe this DNA proximity detection tool has the potential to be adapted for applications involving the proximity and orientation of two DNA sequences.

bioengineering↗

bioRxiv2026

RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness

Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. Significance StatementEndometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis.

physiology↗

bioRxiv2026

Preclinical Safety Evaluation of Human Lactoferrin Alpha (Effera(R))

The preclinical safety of human-equivalent lactoferrin alpha (heqLF; effera(R)), produced by Komagataella phaffii, was evaluated to support its use as a food ingredient in infant formula and products for young children. Genotoxicity was assessed using a bacterial reverse mutation (Ames) assay in five strains of Salmonella typhimurium and Escherichia coli, and an in vitro micronucleus assay in TK6 cells. Both studies followed OECD guidelines and were conducted up to the recommended limit concentrations (5000 {micro}g/plate and 2000 {micro}g/mL, respectively). A 14-day non-GLP juvenile dose range-finding study and a 13-week GLP juvenile rat toxicity study with a 4-week recovery phase were conducted under ICH S11 guidance. Neonatal Sprague-Dawley rats received heqLF at 0, 1500, 3000, or 5000 mg/kg body weight/day by twice-daily oral gavage from postnatal day 7 to 98. Bovine lactoferrin (bLF) and whey protein at 5000 mg/kg body weight/day served as reference controls. heqLF was non-mutagenic and non-clastogenic in both genotoxicity assays. In the 13-week juvenile rat study, no heqLF-related mortality, clinical signs, developmental, neurobehavioral, or immune toxicity effects were observed. Minor, non-adverse renal findings consistent with high protein intake were observed and largely reversed during recovery. Clinical pathology parameters fully resolved during recovery. Toxicokinetic evaluation showed no systemic accumulation. Based on the absence of toxicologically relevant adverse findings, heqLF is well tolerated at doses up to 5000 mg/kg body weight/day, establishing a no observed adverse effect level (NOAEL) of 5000 mg/kg/day, the highest dose tested, and supporting its safety across intended populations from birth to adulthood.

pharmacology and toxicology↗

bioRxiv2026

Extracellular vesicles from wild-type Epstein-Barr virus-transformed B-cells export host DNA and the viral lncRNA EBER1

Epstein-Barr virus (EBV) infection is nearly ubiquitous and strongly linked to multiple sclerosis (MS), but how EBV-infected B cells communicate with distal tissues remains unclear. We performed an integrated multiomic characterization of small extracellular vesicles (sEVs) released from spontaneous lymphoblastoid cell lines (SLCLs) derived from healthy donors and patients with MS, transformed ex vivo by endogenous wild-type EBV. Proteomics identified over 6,000 shared proteins enriched in nucleic acid-binding and chromatin-associated factors. EV-associated DNA resolved into two structurally distinct compartments: DNase-sensitive, high-molecular weight DNA associated with the vesicle corona and DNase-resistant, nucleosome-sized ([~]130-150 bp) DNA. Both compartments were overwhelmingly host-derived and broadly genomically distributed, whereas EBV DNA was minimal. In contrast, viral RNA cargo was dominated by the EBV noncoding RNA EBER1, which was strikingly enriched across all lines and confirmed within individual vesicles by ddPCR and super-resolution microscopy. EBER1 has previously been detected in MS brain tissue, yet its route to the CNS has remained unexplained. Our findings identify sEVs as a plausible vehicle for disseminating this immunostimulatory viral ncRNA beyond sites of latency, pointing to EV-mediated export of EBER1 as a candidate mechanism linking peripheral EBV infection to distal tissue signaling in MS and beyond.

immunology↗

bioRxiv2025

Mind the gap: Understanding discordance between culture- and a non-culture-based measure of bacterial burden in murine tuberculosis treatment models

The standard pharmacodynamic marker in murine tuberculosis drug studies is colony-forming units (CFU). A faster PCR-based marker of bacterial burden is 16S rRNA. For unclear reasons, treatment reduces CFU more than 16S rRNA. We evaluated this CFU-16S gap and estimated the fraction potentially attributable to slow decay of 16S rRNA from dead Mycobacterium tuberculosis (Mtb) versus transition to a viable but not culturable on solid agar (VBNCSA) population. We quantified the CFU-16S gap during and following treatment in six BALB/c mouse studies and one in vitro study. Applying a two-population ordinary differential equation-based model of Mtb death and 16S rRNA decay, we estimated the fraction of the gap potentially attributable to dead Mtb. Using meta-regression, we estimated the association between CFU or 16S rRNA with relapse. For all regimens, CFU fell more than 16S rRNA, ranging from isoniazid-rifampin-pyrazinamide-ethambutol (CFU decreased 39-times more than 16S rRNA at week 4) to bedaquiline-pretomanid-moxifloxacin-pyrazinamide (CFU decreased >500,000-times more). The two-population model suggested that the fraction of the CFU-16S gap attributable to residual 16S rRNA from dead Mtb is modest and decreases over time. After treatment, 16S rRNA often fell while CFU rose. Four-week CFU change explained most variation in relapse (R{superscript 2}=0.90) while four-week 16S rRNA change did not (R{superscript 2}=0.24). CFU-16S gap is only partially explained by slow decay of residual 16S, suggesting development of a VBNCSA population. However, continued decrease in 16S rRNA after treatment cessation and its limited association with relapse suggests VBNCSA may be a transient rather than persistent state.

microbiology↗

bioRxiv2024

Title: 4-week GLP immunotoxicity assessment of lactoferrin alpha produced by Komagataella phaffii in Sprague Dawley rats

Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella Phaffii (effera) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount [~]400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.

pharmacology and toxicology↗

bioRxiv2024

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

BackgroundAnthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated. MethodsThe Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice (Cyp1a1/1a2-/-, Cyp1b1-/-, and Cyp1a1/1a2/1b1-/-). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography. ResultsIn WT mice, Dox treatment was associated with a decrease in Cyp1a2 and increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2-/- and Cyp1a1/1a2/1b1-/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1-/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2-/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection. ConclusionsTaken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.

molecular biology↗

bioRxiv2024

Dose range-finding toxicity study in rats with recombinant human lactoferrin produced in Komagataella phaffii

The oral toxicity of recombinant human lactoferrin (Helaina rhLF, Effera) produced in Komagataella phaffii was investigated in adult Sprague-Dawley rats by once daily oral gavage for 14 consecutive days. The study used groups of 3-6 rats/sex/dose. The vehicle control group received sodium citrate buffer and the test groups received daily doses of 200, 1000 and 2000 mg of rhLF per kg body weight. Bovine LF at 2000 mg/kg body weight per day was used as a comparative control. Clinical observations, body weight, hematology, clinical chemistry, iron parameters, immunophenotyping, and gross examination at necropsy were used as criteria for detecting the effects of treatment in all groups and to inform dose levels for future toxicology studies. Quantitative LF levels were also analyzed as an indication of bioavailability. Overall, administration of Helaina rhLF by once daily oral gavage for 14 days was well tolerated in rats at levels up to 2000 mg/kg/day, or 400x Helainas intended commercial use, and indicating that a high dose of 2000 mg/kg/day is appropriate for future definitive toxicology studies.

pharmacology and toxicology↗

bioRxiv2024

Evaluation of the potential food allergy risks of recombinant human lactoferrin expressed in Komagataella phaffii

Prior to the introduction of novel food ingredients into the food supply, safety risk assessments are required, and numerous prediction models have been developed and validated to evaluate safety. The allergenic risk potential of Helaina recombinant human lactoferrin (rhLF, Effera), produced in Komagataella phaffii (K. phaffii) was assessed by literature search, bioinformatics sequence comparisons to known allergens, glycan allergenicity assessment, and a simulated pepsin digestion model. The literature search identified no allergenic risk for Helaina rhLF, K. phaffii, or its glycans. Bioinformatics search strategies showed no significant risk for cross-reactivity or allergenicity between rhLF or the 36 residual host proteins and known human allergens. Helaina rhLF was also rapidly digested in simulated gastric fluid and its digestibility profile was comparable to human milk lactoferrin (hmLF), further demonstrating a low allergenic risk and similarity to the hmLF protein. Collectively, these results demonstrate a low allergenic risk potential of Helaina rhLF and do not indicate the need for further clinical testing or serum IgE binding to evaluate Helaina rhLF for risk of food allergy prior to introduction into the food supply.

immunology↗

bioRxiv2022

Host-driven temperature dependence of viral infection in honey bees

The temperature dependence of infection reflects changes in the performance of parasites and hosts. High temperatures (i.e., fever) often mitigate infection by favoring heat-tolerant hosts over heat-sensitive parasites. Honey bees exhibit an endothermic, colony-level temperature regulation that is exceptional among insects and favors resistance to several parasites. However, proliferation of viruses is heavily host-dependent, suggesting that viral infection could be linked to--not threatened by--optimum host function. To understand how temperature-driven changes in performance of viruses and hosts shape virus proliferation, we compared the temperature dependence of isolated viral enzyme activity, three honey bee traits, and infection of honey bee pupae. Viral enzyme activity varied by <2-fold over a >30 {degrees}C interval that spanned the temperatures typical of ectothermic insects and honey bees. In contrast, metrics of honey bee performance peaked at high ([≥] 35 {degrees}C) temperatures and were highly temperature-sensitive, with respiration varying 8-fold over a 20 {degrees}C interval and successful development requiring a narrow 8 {degrees}C temperature range. Although these results suggested that hosts would gain a relative advantage over viruses with increasing temperature, the temperature dependence of pupal infection matched that of pupal development, falling only near pupaes upper thermal limits. Our results reflect the host-dependent nature of virus proliferation, suggesting that infection is accelerated--not curtailed--by optimum host function, contradicting predictions of infection based on the relative performance of parasites and hosts, and suggesting tradeoffs between infection resistance and host survival. Despite a 98% reduction in infection at the upper end of the colony temperature range, the narrow thermal safety margin for honey bee development might preclude the effectiveness of fever for controlling viruses.

ecology↗

bioRxiv2022

Instantaneous visual genotyping and facile site-specific transgenesis via CRISPR-Cas9 and phiC31 integrase

The zebrafish Danio rerio has become a popular model in functional genomics and genetic disease studies. However, when a zebrafish mutant line must be propagated as heterozygotes due to homozygous lethality, using standard genotyping methods to identify a population of homozygous mutant embryos is time-consuming and sometimes impractical due to downstream applications such as large-scale chemical screens. Here, we introduce TICIT, Targeted Integration by CRISPR-Cas9 and Integrase Technologies, which utilizes the site-specific DNA recombinase - phiC31 integrase - to insert fluorescent markers into CRISPR-Cas9-generated mutant alleles. It allows instantaneous determination of a zebrafishs genotype simply by examining its color. This technique, which relies on first knocking in a 39-basepair phiC31 landing site via CRISPR-Cas9, enables researchers to insert large DNA fragments at the same genomic location repeatedly and with high precision and efficiency. We demonstrated that TICIT could also be used to create reporter fish driven by an endogenous promoter. Additionally, we created a landing site located in the tyrosinase gene that could support transgene expression in a broad spectrum of tissue and cell types, acting as a putative safe harbor locus. Hence, TICIT can yield predictable and reproducible transgene expression, facilitate diverse applications in zebrafish, and may be applicable to cells in culture and other model organisms.

bioengineering↗

bioRxiv2022

Multi-ancestry GWAS of major depression aids locus discovery, fine-mapping, gene prioritisation, and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from individuals of European ancestry. This includes samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional sample diversity: the number of credible sets with [≤]5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in samples of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large diverse samples for the identification of target genes and putative mechanisms.

genetics↗

bioRxiv2021

Unsupervised deep learning reveals a stimulative effect of dopamine D3 receptor agonists on zebrafish sociality

It has been a major challenge to systematically evaluate and compare how pharmacological perturbations influence social behavioral outcomes. Although some pharmacological agents are known to alter social behavior, precise description and quantification of such effects have proven difficult. The complexity of brain functions regulating sociality makes it challenging to predict drug effects on social behavior without testing in live animals, and most existing behavioral assays are low-throughput and provide only unidimensional readouts of social function. To achieve richer characterization of drug effects on sociality, we developed a scalable social behavioral assay for zebrafish named ZeChat based on unsupervised deep learning. High-dimensional and dynamic social behavioral phenotypes are automatically classified using this method. By screening a neuroactive compound library, we found that different classes of chemicals evoke distinct patterns of social behavioral fingerprints. By examining these patterns, we discovered that dopamine D3 agonists possess a social stimulative effect on zebrafish. The D3 agonists pramipexole, piribedil, and 7-hydroxy-DPAT-HBr rescued social deficits in a valproic acid-induced zebrafish autism model. The ZeChat platform provides a promising approach for dissecting the pharmacology of social behavior and discovering novel social-modulatory compounds.

animal behavior and cognition↗

bioRxiv2019

Elav-mediated exon skipping and alternative polyadenylation of the Dscam1 gene is required for axon outgrowth

Many metazoan genes express alternative long 3' UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3' UTR isoforms due to alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3' UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3' UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon growth in Drosophila. The Dscam1 long 3' UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC=\"FIGDIR/small/613059_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (45K):\norg.highwire.dtl.DTLVardef@1a23558org.highwire.dtl.DTLVardef@5c3dddorg.highwire.dtl.DTLVardef@1e1808forg.highwire.dtl.DTLVardef@1bf3888_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIElav regulates Dscam1 long 3' UTR (Dscam1-L) biogenesis\nC_LIO_LILong-read sequencing reveals connectivity of long 3' UTR to skipping of upstream exon 19\nC_LIO_LILoss of Dscam1-L impairs axon outgrowth\nC_LIO_LIDscam1 long 3' UTR is required for correct splicing of exon 19\nC_LI

molecular biology↗

bioRxiv2018

Analysis of Polygenic Score Usage and Performance across Diverse Human Populations

Studies examining relationships between genotypic and phenotypic variation have historically been carried out on people of European ancestry. Efforts are underway to address this limitation, but until they succeed, the legacy of a Euro-centric bias will continue to hinder research, including the use of polygenic scores, which are individual-level metrics of genetic risk. Ongoing debate surrounds the generalizability of polygenic scores based on genome-wide association studies (GWAS) conducted in European ancestry samples, to non-European ancestry samples. We analyzed the first decade of polygenic scoring studies (2008-2017, inclusive), and found that 67% of studies included exclusively European ancestry participants and another 19% included only East Asian ancestry participants. Only 3.8% of studies were carried out on samples of African, Hispanic, or Indigenous peoples. We find that effect sizes for European ancestry-derived polygenic scores are only 36% as large in African ancestry samples, as in European ancestry samples (t=-10.056, df=22, p=5.5x10-10). Analyzing global populations, we show that relationships between height polygenic scores and height are highly dependent on methodological choices in polygenic score construction, highlighting the need for caution in interpreting population level differences in distributions of polygenic scores, as currently calculated. These findings bolster the rationale for large-scale GWAS in diverse human populations and highlight the need for better handling of linkage disequilibrium and variant frequencies when applying scores to non-European samples.

genetics↗

bioRxiv2017

Pathway-based polygenic risk implicates GO: 17144 drug metabolism in recurrent depressive disorder

The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic, with any top risk loci conferring a very small proportion of variance in case-control status (1). Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways have proved successful in treating MDD. However, it is possible that with information from PGC analyses, examining specific molecular pathway(s) implicated in MDD can further inform our study of molecular drug targets. Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10,640), we derived polygenic risk scores for MDD and for MDD specific to each of over 300 molecular pathways. We then used these data to identify sets of scores significantly predictive of case status, accounting for critical covariates. Over and above global polygenic risk for MDD, polygenic risk within the GO: 17144 drug metabolism pathway significantly predicted recurrent depression. In transcriptomic analyses, two pathway genes yielded suggestive signals at FDR q-values = .054: CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1). Because the neuroleptic carbamazepine is a known inducer of CYP2C19, future research might examine whether drug metabolism PRS has any influence on clinical presentation and treatment response. Overall, results indicate that pathway-based risk might inform treatment of severe depression. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.

genetics↗

bioRxiv2017

Genome-wide Association Study of Clinical Features in the Schizophrenia Psychiatric Genomics Consortium: Confirmation of Polygenic Effect on Negative Symptoms

Schizophrenia is a clinically heterogeneous disorder. Proposed revisions in DSM - 5 included dimensional measurement of different symptom domains. We sought to identify common genetic variants influencing these dimensions, and confirm a previous association between polygenic risk of schizophrenia and the severity of negative symptoms. The Psychiatric Genomics Consortium study of schizophrenia comprised 8,432 cases of European ancestry with available clinical phenotype data. Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. We examined the relationship between the resultant symptom dimensions and aggregate polygenic risk scores indexing risk of schizophrenia. We performed genome - wide association study (GWAS) of each quantitative traits using linear regression and adjusting for significant effects of sex and ancestry. The negative symptom factor was significantly associated with polygene risk scores for schizophrenia, confirming a previous, suggestive finding by our group in a smaller sample, though explaining only a small fraction of the variance. In subsequent GWAS, we observed the strongest evidence of association for the positive and negative symptom factors, with SNPs in RFX8 on 2q11.2 (P = 6.27x10-8) and upstream of WDR72 / UNC13C on 15q21.3 (P = 7.59x10-8), respectively. We report evidence of association of novel modifier loci for schizophrenia, though no single locus attained established genome - wide significance criteria. As this may have been due to insufficient statistical power, follow - up in additional samples is warranted. Importantly, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension.

genetics↗