Biology subjects

Lane, J.

Publications and source records attributed to Lane, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Ultra processed microbiome: Effects of dietary Stable Carbonyl adducts (SCars) on developing microbiota of mice

Consumption of ultra-processed food (UPF) is increasing and is causally linked with noncommunicable disease onset, however specific compounds within UPFs that influence disease risk remain poorly defined. The acronym 'SCars', for Stable Carbonyl Adducts, is introduced herein as an umbrella term encompassing advanced glycation end-products (AGEs), advanced lipoxidation end-products (ALEs), and other carbonyl-derived modifications. These molecules arise as products of spontaneous carbonyl chemistry, a reaction accelerated by industrial food processing. Dietary SCars have been associated with metabolic dysfunction; however, their impact on microbiome composition during windows of developmental vulnerability has not been well studied. Puberty in mice represents a period of developmental plasticity during which the gut microbiome is susceptible to dietary exposures. We tested whether transient exposure to high levels of dietary SCars during puberty remodels the developing gut microbiome. Using metagenomic sequencing of fecal samples from mice exposed to high-SCars or control diets, we found that high-SCars exposure profoundly impacted microbial community structure and metabolic potential. Dietary SCars reduced microbial diversity and depleted short-chain fattyacid producing taxa while enriching pathways related to membrane remodeling, branched-chain amino acid biosynthesis, and nucleotide anabolism. These data identify SCars as features of UPFs capable of reprogramming the developing gut microbiota.

microbiology↗

bioRxiv2026

Maternal effects shape scale-dependent convergence in gut microbial responses to environmental change

Animals can experience environmental variability across multiple temporal scales, from predictable within-year seasonal fluctuations to rarer, irregular resource pulses that occur across generations. While gut microbiome responses to seasonal changes are well documented, far less is understood about how host-associated microbiomes respond to episodic environmental resource pulses, and whether such responses can persist across generations. Here, we investigate how gut microbial communities of wild North American red squirrels (Tamiasciurus hudsonicus) respond to intra-annual seasonal variation and episodic resource pulses happening years apart (specifically, seed masting). We then test the hypothesis that these responses are shared by mothers and their offspring. In line with prior work across mammals, we found that seasonal variation strongly structured gut microbiomes, driving widespread and convergent shifts in composition across the year. However, episodic resource pulses predicted microbial scatter such that gut microbiomes became more dissimilar across individuals in resource pulse years compared to typical years. Despite this population-level divergence, mothers and their adult offspring exhibited microbial convergence when encountering resource pulses occurring years apart, whereas seasonal responses were shared across the population and not unique to mother-offspring pairs. Overall, our results highlight the mammalian gut microbiome as a flexible component of the host phenotype, capable of adjusting to both predictable seasonal variation and large-scale, episodic resource pulses. Patterns of mother-offspring similarity across resource pulse years further provide evidence that some host-microbial responses to environmental change may be transmitted across generations.

ecology↗

bioRxiv2026

Small intestine microbiota development prevents early-life adiposity via IL-22-mediated intestinal PPARα suppression

Perturbation to the early-life microbiota has long-term detrimental effects on health and development, leading to increased risk for metabolic dysfunction and childhood obesity. Despite the central role of the small intestine (SI) in energy balance, the impact of SI microbiota establishment on the regulation of host metabolism and early-life adiposity remains unclear. Here, we report that disruption of a critical SI microbiota-intestinal epithelial cell circuit, specifically during a critical early-life period, drives long-lasting obesity. We demonstrate that the SI microbiota expands in abundance and diversity significantly between 2 and 3 weeks of life, and that segmented filamentous bacteria (SFB) and Lactobacillus intestinalis establish residence. Disruption of the early-life SI microbiota with antibiotics leads to enhanced lipid uptake and adiposity, driven by increased peroxisome proliferator-activated receptor alpha (PPAR) expression and activity in SI epithelial cells (IECs). We demonstrate that SFB and L. intestinalis are key regulators of PPAR in SI IECs by increasing intestinal IL-22 levels specifically during weaning, which is necessary for inhibition of antibiotic-induced adiposity in a PPAR-dependent manner. Together, this work provides mechanistic insights into beneficial microbiota-induced epithelial-immune crosstalk in the SI that is specific to early life, a critical protective mechanism against excessive adiposity in infancy, and offers insight into how antibiotics during infancy may increase the risk of childhood obesity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/731695v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1b32f07org.highwire.dtl.DTLVardef@d4a5a6org.highwire.dtl.DTLVardef@c76d1borg.highwire.dtl.DTLVardef@cc479d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

ACE-031, a Soluble Activin Type IIB Receptor, Increases Muscle Mass and Strength in the Common Marmoset (Callithrix jacchus)

AimPharmacological blockade of ligands for the activin receptor type IIB (ActRIIB) e.g., myostatin and activin A is associated with improvements in murine skeletal muscle mass and function. The efficacy of a similar treatment approach in a non-human primate (NHP) model would suggest a greater likelihood of success in the treatment of humans suffering from chronic myopathies. In the present study, we elucidate the potential therapeutic benefit of ACE-031, a therapeutic protein consisting of the ActRIIB extracellular region fused to human IgG1, in the common marmoset (Callithrix jacchus). MethodsMarmosets were randomized to receive ACE-031 or vehicle control (10 mM Tris buffered saline; TBS) for 14 weeks. Body composition was measured weekly throughout the experimental period and morphometric analysis and contractile properties of skeletal muscle were assessed terminally. ResultsMarmosets administered ACE-031 showed a significant increase in body weight and lean body mass from baseline, while no change was seen in the vehicle-treated controls. Biceps brachii exhibited a significant increase in the cross-sectional area of both type I and type II fibers and ex vivo contractile properties of the EDL showed an increase in absolute and specific force production. ConclusionThe efficacy of ACE-031 in non-human primates provides optimism that a therapeutic strategy that targets multiple negative regulators of skeletal muscle may be beneficial in treating myopathies in humans.

physiology↗

bioRxiv2025

PTPN2-KO CAR-T Cells Demonstrate Enhanced Effector Function, CNS Infiltration, and Toxicity in a Non-Human Primate CAR-T Model

B-cell targeting CAR-T cell therapies achieve high remission rates, yet durable responses occur in fewer than 40% of patients. Deletion of negative T-cell regulators, such as PTPN2, a key inhibitor of TCR and cytokine signaling, represents a promising strategy to enhance the efficacy of CAR-T cells. While transfer of PTPN2 knockout (KO) T cells has demonstrated antitumor benefits in murine models, its impact on human-derived CAR-T cells and, importantly, the associated in vivo efficacy and toxicity remain unclear. Here, we demonstrate that PTPN2-KO human CD19 CAR-T cells exhibit enhanced cytokine production, cytotoxicity, TCR and CAR affinity and signaling, leading to superior in vitro elimination of leukemic cells with low CD19 expression. To assess in vivo efficacy and toxicity, we performed a dose-escalation study using a non-human primate (NHP) model of B-cell-targeting CD20 CAR-T cell therapy. We demonstrated that PTPN2-KO CD20 CAR-T cells exhibited superior in vivo expansion and B-cell depletion compared to WT CAR-T cells, in a dose-dependent manner. At the highest dose level, CAR-T expansion was associated with increased toxicities, particularly ICANS, compared to PTPN2 WT CD20 CAR-T cells driven by enhanced CNS-infiltration. Transcriptional profiling revealed a dominant effector and proliferative signature, with cytotoxic CNS-infiltrating CD8+ PTPN2-KO CAR-T cells implicated in ICANS pathogenesis. This study details the comprehensive evaluation of PTPN2-KO CAR-T cells in an immunocompetent model, demonstrating their enhanced on-target functionality, while highlighting increased toxicity risks, underscoring the need for rigorous preclinical assessment of potent genetic modifications in CAR-T therapy. Key pointsO_LIPTPN2-KO CAR-T cells exhibit enhanced effector function C_LIO_LIIn a dose escalation study in rhesus macaques, PTPN2-KO mediated enhanced proliferation and CNS infiltration was associated with increased ICANS C_LI

immunology↗

bioRxiv2025

Characterisation of lmx1b paralogues in zebrafish reveals divergent roles in skeletal, kidney, and muscle development

LMX1B, a LIM-homeodomain family transcription factor, plays critical roles in the development of multiple tissues, including limbs, eyes, kidneys, brain, and spinal cord. Mutations in the human LMX1B gene cause the rare autosomal-dominant disorder, Nail-patella syndrome which affects development of limbs, eyes, brain, and kidneys. In zebrafish, lmx1b has two paralogues: lmx1ba and lmx1bb. While lmx1b morpholino data exists, stable mutants were previously lacking. Here we describe the characterisation of lmx1b stable mutant lines, with a focus on development of tissues which are affected in Nail-patella syndrome. We demonstrate that the lmx1b paralogues have divergent developmental roles in zebrafish, with lmx1ba affecting skeletal and neuronal development, and lmx1bb affecting renal development. The double mutant, representing loss of both paralogues (lmx1b dKO) showed a stronger phenotype which included additional defects to trunk muscle patterning, and a failure to fully inflate the notochord leading to a dramatic reduction in body length. Overall, these mutant lines demonstrate the utility of zebrafish for modelling Nail- patella syndrome and describe a previously undescribed role for lmx1b in notochord cell inflation. SUMMARY STATEMENTZebrafish lmx1ba and lmx1bb knockout lines exhibit paralogue-specific roles in cartilage, renal, muscle, and notochord development, establishing zebrafish as a viable model for dissecting LMX1B- related pathologies such as Nail-patella syndrome.

developmental biology↗

bioRxiv2025

ADCY3 Ser107Pro links difficulty awakening in the morning to adiposity through circadian regulation of adipose thermogenesis

Modern lifestyles often disturb circadian rhythms, yet the genetic circuits that convert this stress into metabolic dysfunction remain poorly defined. Here, we identify a missense variant in ADCY3 (rs11676272; Ser107Pro) as a pleiotropic regulator of circadian preference and adiposity. Using genome-wide pleiotropy analysis in [~]480,000 UK Biobank participants, we show that the G risk allele (Pro107) increases morningness, BMI, and fat mass in European (N=451,324) and African (N=8,738) ancestry groups, with behavioral amplification by morning difficulty awakening observed in Europeans, power limited interaction modeling in other populations. Structural modeling and transcriptomic analysis suggest this allele destabilizes ADCY3 and alters adipose-specific splicing and expression. In mice, Adcy3 is rhythmically expressed in adipose tissue, with the conserved Pro107 site showing BMAL1 binding and cold-inducible activation. Human adipose ADCY3 expression also increases after weight loss. Together, these findings reveal a genotype-dependent, behaviorally modifiable axis linking difficulty awakening to adipose thermogenesis and obesity risk.

genomics↗

bioRxiv2024

Using SAFEPATH to Uncover a Novel Mechanism of Hepatotoxicity for Gefitinib

This white paper details the research conducted by Ignota Labs using their advanced causal and explainable AI technology, SAFEPATH, to analyse the mechanisms of hepatotoxicity for two EGFR-TKI inhibitors, Erlotinib and Gefitinib, the latter having an as yet unknown mechanism of toxicity. The known mechanism of UGT1A1-mediated toxicity of Erlotinib was recovered, and a novel sphingolipid metabolism mechansim of toxicity of Gefitinib was hypothesised and subsequently experimentally validated. Crucially, we were also able to suggest the reason for the observed heterogeneous toxicity response to Gefitinib. This study exemplifies the potential of integrating AI tools with comprehensive datasets to improve drug safety and patient management.

systems biology↗

bioRxiv2024

Evaluation of Methodologies in Anti-nephrin Autoantibody Detection

Recent studies discovered the prominent presence of anti-nephrin autoantibodies in minimal change disease, steroid-sensitive nephrotic syndrome and/or post-transplant recurrent focal segmental glomerulosclerosis (FSGS). However, widely different, and often unconventional autoantibody detection methods were used among these studies, making it challenging to assess the pathogenic role for the antibodies. Here we examined methods of conventional ELISA, magnetic on-beads ELISA, immunoprecipitation-immunoblotting (IP-IB), and cell- and tissue-based antibody assays with 127 plasma samples of kidney and non-kidney diseases. On the antigen side, we compared commercially available recombinant human nephrin extracelluar domain (ECD) produced from human or mouse cell lines, as well as lab-made full length, ECD, and series of ECD truncates for measuring autoantibody reactivity and specificity. Surprisingly, different assay methods and different antigen preparations led to observation of assay-specific false-positive and false-negative results. In general, a set of tests that combines magnetic beads-enhanced ELISA, followed by IP-IB, and epitope mapping showed the most robust results for anti-nephrin autoantibodies, detected in two primary FSGS patients among all cases tested. It is interesting to note that cell/tissue-based results, also supported by antigen truncation studies, clearly suggest steric hindrance of reactive epitopes, as in full length nephrin that forms compact self-associated complexes. In conclusion, anti-nephrin positivity is rare among the tested patients (2/127), including those with FSGS (2/42), and autoantibody results can be affected by the choice of detection methods.

biochemistry↗

bioRxiv2024

Influence of predation mortality on past and future dynamics of Pacific Herring: implications for stock status and future biomass

The recovery of marine mammals from historical over-exploitation in the 1970s represents one of the largest changes in trophic structure in the northeast Pacific Ocean over the last century, for which the impacts on key forage species such as Pacific Herring (Clupea pallasii) are poorly understood. This has prompted hypotheses that increasing marine mammal populations are the primary cause for productivity declines for some fish stocks and their lack of recovery to historical abundance levels. In this study, we evaluate such a hypothesis for Pacific Herring by quantifying historical predation rates by key predators including cetaceans (Pacific Humpbacks, Grey Whales), pinnipeds (Stellar Sea Lions, Harbour Seals), and piscivorous fish (Pacific Hake). Predation mortality is quantified via a novel approach that integrates a single-species catch-at-age model with estimates of predator consumption derived from bioenergetic models. We found that predator consumption, largely driven by Humpback Whales, explained increasing Pacific Herring natural mortality rates in recent years and could be used to forecast future mortality. Incorporating higher future natural mortality rates produced higher estimates of current stock status (1.09-1.2B0) based on lower estimates of equilibrium unfished biomass (17.5-20.3 kt). Conversely, models that assumed mortality was more like the historical average had lower stock status (0.63B0) and higher estimates of unfished biomass (32.4 kt). We demonstrate a practical approach for ecosystem modelling that can be used to develop operating model scenarios for management strategy evaluation, improving scientific defensibility by removing an element of analyst choice for future mortality scenarios. We discuss how simpler modifications to single-species model assumptions can be more pragmatic for providing fisheries management advice, while more complex multi-species or ecosystem models might provide more nuanced insights for exploring research questions related to multi-species ecosystems and fisheries interactions.

ecology↗

bioRxiv2023

B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients

There is growing appreciation for the emergence of CARneg bystander T cells after CAR-T cell infusion. However, their phenotypic and transcriptomic hallmarks and mechanisms of activation remain uncertain. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T cells to interrogate CARneg T cells following B cell targeted CAR-T cell therapy. In a NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisangelecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T cells. These T cells efficiently killed leukemic cells through a TCR-independent mechanism. Together, these data identify bystander CD8+ T cells as a novel mechanism by which CAR-T cell infusion can induce further anti-leukemic activity, measurable in both NHP and in patients. Statement of SignificanceWe have deeply interrogated CARneg bystander CD8+ T cells during CAR-T cell expansion in non{-}human primates and patients receiving Tisangelecleucel to identify the unique transcriptomic signature defining these cells, and to determine that IL-2-and IL-15-induced cytotoxic bystander T cells are capable of killing in a TCR-independent manner. These data highlight the potential of bystander T cells for leukemia control and provide a critical foundation for their future analysis.

immunology↗

bioRxiv2023

Respiratory syncytial virus directly binds miR-26, miR-27, and let-7 to de-repress gene targets through canonical and non-canonical mechanisms

microRNAs (miRNAs) regulate nearly all physiological processes but our understanding of exactly how they function remains incomplete, particularly in the context of viral infections. Here we adapt a biochemical method (CLEAR-CLIP) and analysis pipeline to identify targets of miRNAs in lung cells infected with Respiratory syncytial virus (RSV). We show that RSV binds directly to miR-26 and miR-27 through seed pairing and demonstrate that these miRNAs target distinct gene networks associated with cell cycle and metabolism (miR-27) and antiviral immunity (miR-26). Many of the targets are de-repressed upon infection and we show that the miR-27 targets most sensitive to miRNA inhibition are those associated with cell cycle. Finally, we demonstrate that high confidence chimeras for miR-26 and miR-27 also map to regulatory regions. We validate that a proportion of miR-27 and Argonaute 2 (AGO2) is nuclear in infected cells and identify a long non-coding RNA (lncRNA) as a miR-27 target that is linked to transcriptional regulation of nearby genes. This work expands the target networks of miR-26 and miR-27 to include direct interactions with RSV and lncRNAs and implicate these miRNAs in regulation of key genes that impact the viral life cycle associated with cell cycle, metabolism, and antiviral immunity.

molecular biology↗

bioRxiv2023

Interpretation of body condition index should be informed by natural history

Many studies assume that it is beneficial for individuals of a species to be heavier, or have a higher body condition index (BCI), without accounting for the physiological relevance of variation in the composition of different body tissues. We hypothesized that the relationship between BCI and masses of physiologically important tissues (fat and lean) would be conditional on annual patterns of energy acquisition and expenditure. We studied three species with contrasting ecologies in their respective natural ranges: an obligate hibernator (Columbian ground squirrel, Urocitellus columbianus), a facultative hibernator (black-tailed prairie dog, Cynomys ludovicianus), and a food-caching non-hibernator (North American red squirrel, Tamiasciurus hudsonicus). We measured fat and lean mass in adults of both sexes using quantitative magnetic resonance (QMR). We measured body mass and two measures of skeletal structure (zygomatic width and right hind foot length) to develop sex- and species-specific BCIs, and tested the utility of BCI to predict body composition in each species. Body condition indices were more consistently, and more strongly correlated, with lean mass than fat mass. The indices were most positively correlated with fat when fat was expected to be very high (pre-hibernation prairie dogs). In all cases, however, BCI was never better than body mass alone in predicting fat or lean mass. While the accuracy of BCI in estimating fat varied across the natural histories and annual energetic patterns of the species considered, measuring body mass alone was as effective, or superior in capturing sufficient variation in fat and lean in most cases.

physiology↗

bioRxiv2022

Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates

Notch signaling promotes T-cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess if Notchs effects are evolutionarily conserved and identify key mechanisms, we studied antibody-mediated DLL4 blockade in a non-human primate model similar to human allo-HCT. Short-term DLL4 blockade improved post-transplant survival with striking, durable protection from gastrointestinal GVHD, out of proportion to other disease sites. Unlike prior immunosuppressive strategies, anti-DLL4 interfered with a T-cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin a4b7 in conventional T-cells via b1 competition for a4 binding, while preserving a4b7 in regulatory T-cells. Thereby, DLL4/Notch blockade decreased effector T-cell infiltration into the gut, with increased regulatory to conventional T-cell ratios early after allo-HCT. Our results identify a conserved, biologically unique and targetable role of DLL4/Notch signaling in GVHD. One Sentence SummaryNotch signaling promotes pathogenic effector T cell infiltration of the intestine during acute graft-versus-host disease.

immunology↗

bioRxiv2022

Multi-ancestry genome-wide analysis identifies common genetic variants for self-reported sleep duration and shared genetic effects

Both short and long sleep duration are associated with increased risk of chronic diseases, but the genetic determinants of sleep duration are largely unknown outside of European populations. Here we report transferability of a polygenic score of 78 European ancestry sleep duration SNPs to an African (n=7,288; p=0.003), a South Asian (n=7,485; p=0.025), and a Japanese (n=13,618; p=6x10-4) cohort, but not to a cohort of Hispanic/Latino (n- XXX; p=0.71) participants. Furthermore, in a pan-ancestry (N = 483,235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 5 novel and 68 known loci are associated with genome-wide significance. For the novel loci, sleep duration signals colocalize with expression-QTLs for PRR12 and COG5 in brain tissues, and pleiotropic associations are observed with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

genomics↗

bioRxiv2021

Benefits of living closer to kin vary by genealogical relationship in a territorial mammal

While cooperative interactions among kin are a key building block in the societies of group-living species, their importance for species with more variable social environments is unclear. North American red squirrels (Tamiasciurus hudsonicus) defend individual territories in dynamic neighbourhoods and are known to benefit from living among familiar conspecifics, but not relatives. However, kin-directed behaviours may be restricted to specific genealogical relationships or strongly mediated by geographic distance, masking their influence at broader scales. Using distance between territories as a proxy for the ability of individuals to interact, we estimated the influence of primary kin (parents, offspring, siblings) on the annual survival and reproductive success of red squirrels. This approach revealed associations between fitness and access to kin, but only for certain genealogical relationships and fitness components. For example, females had enhanced annual survival when living closer to their daughters, though the reverse was not true. Most surprising was the finding that males had higher annual reproductive success when living closer to their father, suggesting possible recognition and cooperation among fathers and sons. Together, these findings point to unexpected nuance in the fitness consequences of kinship dynamics for a species that is territorial and largely solitary.

animal behavior and cognition↗

bioRxiv2021

Using a Homeogram to Detect Sleep in Free-living Animals

O_LISleep is appreciated as a behavior critical to homeostasis, performance, and fitness. Yet, most of what we know about sleep comes from humans or controlled laboratory experiments. Assessing sleep in wild animals is challenging, as it is often hidden from view, and electrophysiological recordings that define sleep states are difficult to obtain. Accelerometers have offered great insight regarding gross movement, although ambiguous quiescent states like sleep have been largely ignored, limiting our understanding of this ubiquitous behavior. C_LIO_LIWe developed a broadly applicable sleep detection method called a homeogram that can be applied to accelerometer data collected from wild animals. We applied our methodology to detect sleep in free-ranging North American red squirrels (Tamiasciurus hudsonicus) in a region that experiences drastic seasonal shifts in light, temperature, and behavioral demands. C_LIO_LIOur method characterized sleep in a manner consistent with limited existing studies and expanded those observations to provide evidence that red squirrels apply unique sleep strategies to cope with changing environments. C_LIO_LIApplying our analytical strategy to accelerometer data from other species may open new possibilities to investigate sleep patterns for researchers studying wild animals. C_LI

animal behavior and cognition↗

bioRxiv2021

Genome-wide analysis of mitochondrial DNA copy number reveals multiple loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses were used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 x 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 x 10-8) and mtDNA replication (p = 1.2 x 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 x 10-4).

genetics↗