Anatomic position determines oncogenic specificity in melanoma.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Inter-mosaic coordination of retinal receptive fields.

The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain1-4. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature5. Here we use a model of efficient coding6 to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.

Neural dynamics underlying birdsong practice and performance.

Musical and athletic skills are learned and maintained through intensive practice to enable precise and reliable performance for an audience. Consequently, understanding such complex behaviours requires insight into how the brain functions during both practice and performance. Male zebra finches learn to produce courtship songs that are more varied when alone and more stereotyped in the presence of females1. These differences are thought to reflect song practice and performance, respectively2,3, providing a useful system in which to explore how neurons encode and regulate motor variability in these two states. Here we show that calcium signals in ensembles of spiny neurons (SNs) in the basal ganglia are highly variable relative to their cortical afferents during song practice. By contrast, SN calcium signals are strongly suppressed during female-directed performance, and optogenetically suppressing SNs during practice strongly reduces vocal variability. Unsupervised learning methods4,5 show that specific SN activity patterns map onto distinct song practice variants. Finally, we establish that noradrenergic signalling reduces vocal variability by directly suppressing SN activity. Thus, SN ensembles encode and drive vocal exploration during practice, and the noradrenergic suppression of SN activity promotes stereotyped and precise song performance for an audience.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation.

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.

Performance of somatic structural variant calling in lung cancer using Oxford Nanopore sequencing technology.

BACKGROUND: Lung cancer is a heterogeneous disease and the primary cause of cancer-related mortality worldwide. Somatic mutations, including large structural variants, are important biomarkers in lung cancer for selecting targeted therapy. Genomic studies in lung cancer have been conducted using short-read sequencing. Emerging long-read sequencing technologies are a promising alternative to study somatic structural variants, however there is no current consensus on how to process data and call somatic events. In this study, we preformed whole genome sequencing of lung cancer and matched non-tumour samples using long and short read sequencing to comprehensively benchmark three sequence aligners and seven structural variant callers comprised of generic callers (SVIM, Sniffles2, DELLY in generic mode and cuteSV) and somatic callers (Severus, SAVANA, nanomonsv and DELLY in somatic modes). RESULTS: Different combinations of aligners and variant callers influenced somatic structural variant detection. The choice of caller had a significant influence on somatic structural variant detection in terms of variant type, size, sensitivity, and accuracy. The performance of each variant caller was assessed by comparing to somatic structural variants identified by short-read sequencing. When compared to somatic structural variants detected with short-read sequencing, more events were detected with long-read sequencing. The mean recall of somatic variant events identified by long-read sequencing was higher for the somatic callers (72%) than generic callers (53%). Among the somatic callers when using the minimap2 aligner, SAVANA and Severus achieved the highest recall at 79.5% and 79.25% respectively, followed by nanomonsv with a recall of 72.5%. CONCLUSION: Long-read sequencing can identify somatic structural variants in clincal samples. The longer reads have the potential to improve our understanding of cancer development and inform personalized cancer treatment.

Germline copy number variants and endometrial cancer risk.

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

The incidence of early onset colorectal cancer in Aotearoa New Zealand: 2000-2020.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC), diagnosed before age 50, has been rising in many countries in the past few decades. This study aims to evaluate this trend in Aotearoa New Zealand and assess its impact on Maori. METHODS: Crude incidence and age-standardized incidence of colorectal cancer (CRC) was analyzed from all new cases from the Aotearoa New Zealand national cancer registry for the period 2000-2020. Trends were estimated by sex, ethnicity, age group and location of cancer and projections made to 2040. RESULTS: Between 2000 and 2020, there were a total of 56,761 cases of CRC diagnosed in Aotearoa New Zealand, 3,702 of these being EOCRC, with age-standardized incidence decreasing significantly (P = 8.2 × 10- 80) from 61.0 to 47.3 cases per 100,000. EOCRC incidence increased on average by 26% per decade (incidence rate ratio (IRR) 1.26, p = < 0.0001) at all sites (proximal colon, distal colon and rectum), while the incidence in those aged 50-79 years decreased on average by 18% per decade (IRR 0.82, p = < 0.0005), again across all sites. There was no significant average change in CRC incidence in those over 80 years. In Maori, there was no significant change in age-standardized incidence. There was however a significant increase in crude incidence rates (IRR 1.28, p = < 0.0005) driven by significant increases in EOCRC (IRR1.36, p = < 0.0005). By 2040, we predict the incidence of EOCRC will have risen from 8.00 to 14.9 per 100,000 (6.33 to 10.00 per 100,000 in Maori). However, due to the aging population an estimated 43.0% of all CRC cases will be diagnosed in those over 80 years of age (45.9% over 70 years of age in Maori). CONCLUSION: The age-standardized incidence of CRC from 2000 to 2020 decreased in Aotearoa New Zealand, but not for Maori. The incidence of EOCRC over the same period continues to rise, and at a faster rate in Maori. However, with the ageing of the population in Aotearoa New Zealand, and for Maori, CRC in the elderly will continue to dominate case numbers.

Generative models of birdsong learning link circadian fluctuations in song variability to changes in performance.

Learning skilled behaviors requires intensive practice over days, months, or years. Behavioral hallmarks of practice include exploratory variation and long-term improvements, both of which can be impacted by circadian processes. During weeks of vocal practice, the juvenile male zebra finch transforms highly variable and simple song into a stable and precise copy of an adult tutor's complex song. Song variability and performance in juvenile finches also exhibit circadian structure that could influence this long-term learning process. In fact, one influential study reported juvenile song regresses towards immature performance overnight, while another suggested a more complex pattern of overnight change. However, neither of these studies thoroughly examined how circadian patterns of variability may structure the production of more or less mature songs. Here we relate the circadian dynamics of song maturation to circadian patterns of song variation, leveraging a combination of data-driven approaches. In particular we analyze juvenile singing in learned feature space that supports both data-driven measures of song maturity and generative developmental models of song production. These models reveal that circadian fluctuations in variability lead to especially regressive morning variants even without overall overnight regression, and highlight the utility of data-driven generative models for untangling these contributions.

Scene statistics and noise determine the relative arrangement of receptive field mosaics.

Many sensory systems utilize parallel ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways consist of ensembles or grids of ON and OFF detectors spanning sensory space. Yet, encoding by opponent pathways raises a question: How should grids of ON and OFF detectors be arranged to optimally encode natural stimuli? We investigated this question using a model of the retina guided by efficient coding theory. Specifically, we optimized spatial receptive fields and contrast response functions to encode natural images given noise and constrained firing rates. We find that the optimal arrangement of ON and OFF receptive fields exhibits a transition between aligned and antialigned grids. The preferred phase depends on detector noise and the statistical structure of the natural stimuli. These results reveal that noise and stimulus statistics produce qualitative shifts in neural coding strategies and provide theoretical predictions for the configuration of opponent pathways in the nervous system.

Neural Support for Contributions of Utility and Narrative Processing of Evidence in Juror Decision Making.

Efforts to explain complex human decisions have focused on competing theories emphasizing utility and narrative mechanisms. These are difficult to distinguish using behavior alone. Both narrative and utility theories have been proposed to explain juror decisions, which are among the most consequential complex decisions made in a modern society. Here, we asked jury-eligible male and female subjects to rate the strength of a series of criminal cases while recording the resulting patterns of brain activation. We compared patterns of brain activation associated with evidence accumulation to patterns of brain activation derived from a large neuroimaging database to look for signatures of the cognitive processes associated with different models of juror decision-making. Evidence accumulation correlated with multiple narrative processes, including reading and recall. Of the cognitive processes traditionally viewed as components of utility, activation patterns associated with uncertainty, but not value, were more active with stronger evidence. Independent of utility and narrative, activations linked to reasoning and relational logic also correlated with increasing evidence. Hierarchical modeling of cognitive processes associated with evidence accumulation supported a more prominent role for narrative in weighing evidence in complex decisions. However, utility processes were also associated with evidence accumulation. These complementary findings support an emerging view that integrates utility and narrative processes in complex decisions.SIGNIFICANCE STATEMENT The last decade has seen a sharply increased interest in narrative as a central cognitive process in human decision-making and as an important factor in the evolution of human societies. However, the roles of narrative versus utility models of decision-making remain hotly debated. While available models frequently produce similar behavioral predictions, they rely on different cognitive processes and so their roles can be separated using the right neural tests. Here, we use brain imaging during mock juror decisions to show that cognitive processes associated with narrative, and to a lesser extent utility, were engaged while subjects evaluated evidence. These results are consistent with interactions between narrative and utility processes during complex decision-making.

Risk of colorectal cancer in patients with appendicitis over the age of 40 years.

AIM: Acute appendicitis in late adulthood is hypothesized to be associated with an increased risk of colorectal cancer (CRC). This study aimed to establish whether patients over the age of 40 years presenting with appendicitis had an increased risk of being diagnosed with CRC over the subsequent 3 years. METHOD: This is a retrospective review of patients aged 40 years and over presenting to Canterbury District Health Board with appendicitis from January 2010 to December 2015. Clinical details were obtained for these patients and cross-referenced with the New Zealand Cancer Registry for the 3 years following diagnosis. The incidence ratio rate (IRR) and standardized incidence ratio (SIR) were calculated by establishing the incidence of CRC in this cohort and comparing it with the Canterbury population data. RESULTS: A total of 1099 patients met the inclusion criteria. The majority (75%) underwent CT as part of their initial work-up. The rate of colonoscopy increased with age from around 10% between 40 and 49 years to 27% for those 70 years and over. Eleven cases of CRC were identified, resulting in an IRR 2.35 (95% CI 1.17-4.21). The SIR for this population was 3.28 (95% CI 1.82-5.92). CONCLUSION: The rate of CRC is significantly increased compared with the background population in this cohort. The results of this study support luminal investigation of adults aged 40 years and over who present with acute appendicitis as CT alone was insufficient to detect the pathology.

Whole-genome landscapes of major melanoma subtypes.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Dynamic density functional theory for sedimentation processes on complex domains: Modelling, spectral elements, and control problems.

Modelling of many real-world processes, such as drug delivery, wastewater treatment, and pharmaceutical production, requires accurate descriptions of the dynamics of hard particles confined in complicated domains. In particular, when modelling sedimentation processes or systems with driven flows, it is important to accurately capture volume exclusion effects. This work applies Dynamic Density Functional Theory to the evolution of a particle density under diffusion, external forces, particle-particle interaction, and volume exclusion. Using a spectral element framework, for the first time it is possible to include all of these effects in dynamic simulations on complex domains. Moreover, this allows one to apply complicated no-flux, and other non-local, non-linear, boundary conditions. The methodology is also extended to control problems, addressing questions of how to enhance production set-up in industrially-motivated processes. In this work the relevant models are introduced, numerical methods are discussed, and several example problems are solved to demonstrate the methods' versatility. It is shown that incorporating volume exclusion is crucial for simulation accuracy and we illustrate that the choice of boundary conditions significantly impacts the dynamics.

Whole Genome Sequencing in Advanced Lung Cancer can be Performed Using Diff-Quik Cytology Smears Derived from Endobronchial Ultrasound, Transbronchial Needle Aspiration (EBUS TBNA).

INTRODUCTION: Maximising alternative sample types for genomics in advanced lung cancer is important because bronchoscopic samples may sometimes be insufficient for this purpose. Further, the clinical applications of comprehensive molecular analysis such as whole genome sequencing (WGS) are rapidly developing. Diff-Quik cytology smears from EBUS TBNA is an alternative source of DNA, but its feasibility for WGS has not been previously demonstrated. METHODS: Diff-Quik smears were collected along with research cell pellets. RESULTS: Tumour content of smears were compared to research cell pellets from 42 patients, which showed good correlation (Spearman correlation 0.85, P < 0.0001). A subset of eight smears underwent WGS, which presented similar mutation profiles to WGS of the matched cell pellet. DNA yield was predicted using a regression equation of the smears cytology features, which correctly predicted DNA yield > 1500 ng in 7 out of 8 smears. CONCLUSIONS: WGS of commonly collected Diff-Quik slides is feasible and their DNA yield can be predicted.

A Network Comprised of miR-15b and miR-29a Is Involved in Vascular Endothelial Growth Factor Pathway Regulation in Thymus Adipose Tissue from Elderly Ischemic Cardiomyopathy Subjects.

As the human thymus ages, it undergoes a transformation into adipose tissue known as TAT. Interestingly, in previous research, we observed elevated levels of vascular endothelial growth factor A (VEGFA) in TAT from patients with ischemic cardiomyopathy (IC), particularly in those over 70 years old. Moreover, in contrast to subcutaneous adipose tissue (SAT), TAT in elderly individuals exhibits enhanced angiogenic properties and the ability to stimulate tube formation. This makes TAT a promising candidate for angiogenic therapies and the regeneration of ischemic tissues following coronary surgery. MicroRNAs (miRNAs) have emerged as attractive therapeutic targets, especially those that regulate angiogenic processes. The study's purpose is to determine the miRNA network associated with both the VEGFA pathway regulation and the enrichment of age-linked angiogenesis in the TAT. RT-PCR was used to analyze angiogenic miRNAs and the expression levels of their predicted target genes in both TAT and SAT from elderly and middle-aged patients treated with coronary artery bypass graft surgery. miRTargetLink Human was used to search for miRNAs and their target genes. PANTHER was used to annotate the biological processes of the predicted targets. The expression of miR-15b-5p and miR-29a-3p was significantly upregulated in the TAT of elderly compared with middle-aged patients. Interestingly, VEGFA and other angiogenic targets were significantly upregulated in the TAT of elderly patients. Specifically: JAG1, PDGFC, VEGFA, FGF2, KDR, NOTCH2, FOS, PDGFRA, PDGFRB, and RHOB were upregulated, while PIK3CG and WNT7A were downregulated. Our results provide strong evidence of a miRNA/mRNA interaction network linked with age-associated TAT angiogenic enrichment in patients with IC.

Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions.

The clinical classification of variants may change with new information, however, there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant data from ClinVar between January 2015 and July 2021. The ClinVar-assigned "aggregate" classification of variants in 121 hereditary cancer genes was harmonized across releases to align to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology terms. Aggregate classification categories were grouped as: benign/likely benign (B/LB); likely pathogenic/pathogenic (LP/P); variant of uncertain significance (VUS); conflicting interpretations of pathogenicity (Conflicting); or Other. We profiled changes in aggregate variant classification between consecutive semi-annual ClinVar releases. The proportion of variants that changed aggregate classification between semi-annual ClinVar releases ranged from 0.6% to 6.4%. The most frequent changes were "VUS to conflicting," "other to LP/P," and "B/LB to Conflicting." A limited number of variants changed aggregate classification from "LP/P to B/LB," or vice versa. Our analysis indicates need for regular reassessment of clinical variant interpretations. The parser developed for this project will facilitate extraction of relevant interpretation data from ClinVar.

Coherent Coupling of Two Remote Magnonic Resonators Mediated by Superconducting Circuits.

We demonstrate microwave-mediated distant magnon-magnon coupling on a superconducting circuit platform, incorporating chip-mounted single-crystal Y_{3}Fe_{5}O_{12} (YIG) spheres. Coherent level repulsion and dissipative level attraction between the magnon modes of the two YIG spheres are demonstrated. The former is mediated by cavity photons of a superconducting resonator, and the latter is mediated by propagating photons of a coplanar waveguide. Our results open new avenues toward exploring integrated hybrid magnonic networks for coherent information processing on a quantum-compatible superconducting platform.

The latitude gradient for multiple sclerosis prevalence is established in the early life course.

The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females.

DNA methylation analysis using bisulphite-based amplicon sequencing of individuals exposed to maternal tobacco use during pregnancy, and offspring conduct problems in childhood and adolescence.

Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem (CP) has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence has been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and offspring CP, to determine whether offspring CP is mediated by tobacco exposure-induced DNA methylation differences. Understanding the etiology of the association between maternal tobacco use and offspring CP will be crucial in the early identification and treatment of CP in children and adolescents. Here, a sub group of N =96 individuals was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Whole blood samples underwent bisulphite-based amplicon sequencing at 10 loci known to play a role in neurodevelopment, or which had associations with CP phenotypes. We identified significant (P CYP1A1 , ASH2L and MEF2C in individuals with CP who were exposed to tobacco in utero . We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/adolescent CP. However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further.