CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3'-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10-6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10-5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10-4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource.

The impact of digital technology in care homes on unplanned secondary care usage and associated costs.

BACKGROUND: A substantial number of Emergency Department (ED) attendances by care home residents are potentially avoidable. Health Call Digital Care Homes is an app-based technology that aims to streamline residents' care by recording their observations such as vital parameters electronically. Observations are triaged by remote clinical staff. This study assessed the effectiveness of the Health Call technology to reduce unplanned secondary care usage and associated costs. METHODS: A retrospective analysis of health outcomes and economic impact based on an intervention. The study involved 118 care homes across the North East of UK from 2018 to 2021. Routinely collected NHS secondary care data from County Durham and Darlington NHS Foundation Trust was linked with data from the Health Call app. Three outcomes were modelled monthly using Generalised Linear Mixed Models: counts of emergency attendances, emergency admissions and length of stay of emergency admissions. A similar approach was taken for costs. The impact of Health Call was tested on each outcome using the models. FINDINGS: Data from 8,702 residents were used in the analysis. Results show Health Call reduces the number of emergency attendances by 11% [6-15%], emergency admissions by 25% [20-39%] and length of stay by 11% [3-18%] (with an additional month-by-month decrease of 28% [24-34%]). The cost analysis found a cost reduction of £57 per resident in 2018, increasing to £113 in 2021. INTERPRETATION: The introduction of a digital technology, such as Health Call, could significantly reduce contacts with and costs resulting from unplanned secondary care usage by care home residents.

'In the shower crying but we came back in the following day and did it all again'. Distress and resilience in care home staff during the COVID-19 pandemic- A qualitative interview study.

BACKGROUND: Care homes (long-term care facilities) were profoundly impacted early in the COVID-19 pandemic, both in terms of resident mortality and restrictions for infection control. This study investigated the impact on the emotional well-being of care home staff of challenges faced at this time, and the strategies used to manage them. METHODS: Semi-structured interviews conducted October 2020-June 2021 with care home staff and health service staff working with them explored the impact of the early waves of the COVID-19 pandemic (March 2020-June 2021). Interview data were analysed using reflexive thematic analysis. RESULTS: Interview participants were 16 care home staff and 10 health service staff. Analysis generated four key themes: 1)Anxiety and distress, 2)Overwhelming workload, 3)Pulling through; and 4)Resilience in a time of crisis. Care home staff experienced Anxiety and distress due to uncertainty of what to expect; witnessing illness and deaths of residents; concerns regarding their own health, and sometimes feeling their work was under-recognised. They also experienced an Overwhelming workload due to infection control measures, caring for sick residents and reduction in external healthcare support. Our theme of Pulling through reflects the peer support and problem-solving strategies with which care home staff managed the impact of the pandemic, along with a sense of responsibility and meaning towards their work. An overarching theme of Resilience in a time of crisis drew on the other three themes and describes how many staff managed, maintained, and often increased their work despite the challenges of the pandemic. Participants also described increasing emotional fatigue as the pandemic continued. CONCLUSIONS: This paper builds on literature on the emotional impact of the pandemic on care home staff, also exploring ways that staff responded to this impact. These findings can help inform planning for future crises including disease outbreaks, and raise important questions for further work to develop pandemic preparedness in care homes and beyond. They also raise wider questions about the current cultural status of care work, which may have exposed care home staff to greater risk of distress, and which contrasts with the professionalism and responsibility shown by staff in response to pandemic challenges.

Understanding health service utilisation patterns for care home residents during the COVID-19 pandemic using routinely collected healthcare data.

BACKGROUND: Healthcare in care homes during the COVID-19 pandemic required a balance, providing treatment while minimising exposure risk. Policy for how residents should receive care changed rapidly throughout the pandemic. A lack of accessible data on care home residents over this time meant policy decisions were difficult to make and verify. This study investigates common patterns of healthcare utilisation for care home residents in relation to COVID-19 testing events, and associations between utilisation patterns and resident characteristics. METHODS: Datasets from County Durham and Darlington NHS Foundation Trust including secondary care, community care and a care home telehealth app are linked by NHS number used to define daily healthcare utilisation sequences for care home residents. We derive four 10-day sets of sequences related to Pillar 1 COVID-19 testing; before [1] and after [2] a resident's first positive test and before [3] and after [4] a resident's first test. These sequences are clustered, grouping residents with similar healthcare patterns in each set. Association of individual characteristics (e.g. health conditions such as diabetes and dementia) with healthcare patterns are investigated. RESULTS: We demonstrate how routinely collected health data can be used to produce longitudinal descriptions of patient care. Clustered sequences [1,2,3,4] are produced for 3,471 care home residents tested between 01/03/2020-01/09/2021. Clusters characterised by higher levels of utilisation were significantly associated with higher prevalence of diabetes. Dementia is associated with higher levels of care after a testing event and appears to be correlated with a hospital discharge after a first test. Residents discharged from inpatient care within 10 days of their first test had the same mortality rate as those who stayed in hospital. CONCLUSION: We provide longitudinal, resident-level data on care home resident healthcare during the COVID-19 pandemic. We find that vulnerable residents were associated with higher levels of healthcare usage despite the additional risks. Implications of findings are limited by the challenges of routinely collected data. However, this study demonstrates the potential for further research into healthcare pathways using linked, routinely collected datasets.

Spatio-temporal modelling of referrals to outpatient respiratory clinics in the integrated care system of the Morecambe Bay area, England.

BACKGROUND: Promoting integrated care is a key goal of the NHS Long Term Plan to improve population respiratory health, yet there is limited data-driven evidence of its effectiveness. The Morecambe Bay Respiratory Network is an integrated care initiative operating in the North-West of England since 2017. A key target area has been reducing referrals to outpatient respiratory clinics by upskilling primary care teams. This study aims to explore space-time patterns in referrals from general practice in the Morecambe Bay area to evaluate the impact of the initiative. METHODS: Data on referrals to outpatient clinics and chronic respiratory disease patient counts between 2012-2020 were obtained from the Morecambe Bay Community Data Warehouse, a large store of routinely collected healthcare data. For analysis, the data is aggregated by year and small area geography. The methodology comprises of two parts. The first explores the issues that can arise when using routinely collected primary care data for space-time analysis and applies spatio-temporal conditional autoregressive modelling to adjust for data complexities. The second part models the rate of outpatient referral via a Poisson generalised linear mixed model that adjusts for changes in demographic factors and number of respiratory disease patients. RESULTS: The first year of the Morecambe Bay Respiratory Network was not associated with a significant difference in referral rate. However, the second and third years saw significant reductions in areas that had received intervention, with full intervention associated with a 31.8% (95% CI 17.0-43.9) and 40.5% (95% CI 27.5-50.9) decrease in referral rate in 2018 and 2019, respectively. CONCLUSIONS: Routinely collected data can be used to robustly evaluate key outcome measures of integrated care. The results demonstrate that effective integrated care has real potential to ease the burden on respiratory outpatient services by reducing the need for an onward referral. This is of great relevance given the current pressure on outpatient services globally, particularly long waiting lists following the COVID-19 pandemic and the need for more innovative models of care.

Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data.

CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7 pseudogene (CYP2A6*12, CYP2A6*34). SVs are challenging to genotype due to their complex genetic architecture. Our aims were to develop a reliable protocol for SV genotyping, functionally phenotype known and novel SVs, and investigate the feasibility of CYP2A6 SV imputation from SNP array data in two ancestry populations. European- (EUR; n = 935) and African- (AFR; n = 964) ancestry individuals from smoking cessation trials were genotyped for SNPs using an Illumina array and for CYP2A6 SVs using Taqman copy number (CN) assays. SV-specific PCR amplification and Sanger sequencing was used to characterize a novel SV. Individuals with SVs were phenotyped using the nicotine metabolite ratio, a biomarker of CYP2A6 activity. SV diplotype and SNP array data were integrated and phased to generate ancestry-specific SV reference panels. Leave-one-out cross-validation was used to investigate the feasibility of CYP2A6 SV imputation. A minimal protocol requiring three Taqman CN assays for CYP2A6 SV genotyping was developed and known SV associations with activity were replicated. The first domain swap CYP2A6-CYP2A7 hybrid SV, CYP2A6*53, was identified, sequenced, and associated with lower CYP2A6 activity. In both EURs and AFRs, most SV alleles were identified using imputation (>70% and >60%, respectively); importantly, false positive rates were <1%. These results confirm that CYP2A6 SV imputation can identify most SV alleles, including a novel SV.

Influence of CYP2A6 Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success.

INTRODUCTION: Genetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations. AIMS AND METHODS: Adult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment. RESULTS: Dependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms. CONCLUSIONS: Although nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers. IMPLICATIONS: Variation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

Fine-mapping inflammatory bowel disease loci to single-variant resolution.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Discovering patterns in outpatient neurology appointments using state sequence analysis.

BACKGROUND: Outpatient services in the UK, and in particular outpatient neurology services, are under considerable pressure with an ever-increasing gap between capacity and demand. To improve services, we first need to understand the current situation. This study aims to explore the patterns of appointment type seen in outpatient neurology, in order to identify potential opportunities for change. METHODS: We use State Sequence Analysis (SSA) on routinely collected data from a single neurology outpatient clinic. SSA is an exploratory methodology which allows patterns within sequences of appointments to be discovered. We analyse sequences of appointments for the 18 months following a new appointment. Using SSA we create groups of similar appointment sequence patterns, and then analyse these clusters to determine if there are particular sequences common to different diagnostic categories. RESULTS: Of 1315 patients 887 patients had only one appointment. Among the 428 patients who had more than one appointment a 6 monthly cycle of appointments was apparent. SSA revealed that there were 11 distinct clusters of appointment sequence patterns. Further analysis showed that there are 3 diagnosis categories which have significant influence over which cluster a patient falls into: seizure/epilepsy, movement disorders, and headache. CONCLUSIONS: Neurology outpatient appointment sequences show great diversity, but there are some patterns which are common to specific diagnostic categories. Information about these common patterns could be used to inform the structure of future outpatient appointments.

Outpatient neurology diagnostic coding: a proposed scheme for standardised implementation.

Clinical coding uses a classification system to assign standard codes to clinical terms and so facilitates good clinical practice through audit, service design and research. However, despite clinical coding being mandatory for inpatient activity, this is often not so for outpatient services, where most neurological care is delivered. Recent reports by the UK National Neurosciences Advisory Group and NHS England's 'Getting It Right First Time' initiative recommend implementing outpatient coding. The UK currently has no standardised system for outpatient neurology diagnostic coding. However, most new attendances at general neurology clinics appear to be classifiable with a limited number of diagnostic terms. We present the rationale for diagnostic coding and its benefits, and the need for clinical engagement to develop a system that is pragmatic, quick and easy to use. We outline a scheme developed in the UK that could be used elsewhere.

Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes.

OBJECTIVES: We evaluated multiple genotyping/sequencing approaches in a homologous region of chromosome 19, and investigated associations of two common 3'-UTR CYP2A6 variants with activity in vivo. METHODS: Individuals (n = 1704) of European and African ancestry were phenotyped for the nicotine metabolite ratio (NMR), an index of CYP2A6 activity, and genotyped/sequenced using deep amplicon exon sequencing, SNP array, genotype imputation and targeted capture sequencing. Amplicon exon sequencing was the gold standard to which other methods were compared within-individual for CYP2A6, CYP2A7, CYP2A13, and CYP2B6 exons to identify highly discordant positions. Linear regression models evaluated the association of CYP2A6*1B and rs8192733 genotypes (coded additively) with logNMR. RESULTS: All approaches were ≤2.6% discordant with the gold standard; discordant calls were concentrated at few positions. Fifteen positions were discordant in >10% of individuals, with 12 appearing in regions of high identity between homologous genes (e.g. CYP2A6 and CYP2A7). For six, allele frequencies in our study and online databases were discrepant, suggesting errors in online sources. In the European-ancestry group (n = 935), CYP2A6*1B and rs8192733 were associated with logNMR (P < 0.001). A combined model found main effects of both variants on increasing logNMR. Similar trends were found in those of African ancestry (n = 506). CONCLUSION: Multiple genotyping/sequencing approaches used in this chromosome 19 region contain genotyping/sequencing errors, as do online databases. Gene-specific primers and SNP array probes must consider gene homology; short-read sequencing of related genes in a single reaction should be avoided. Using improved sequencing approaches, we characterized two gain-of-function 3'-UTR variants, including the relatively understudied rs8192733.

Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn's disease via altered methylation and expression of EPHB4-a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10-4), Crohn's disease (rg = 0.097 ± 0.06, P = 3.27 × 10-3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10-3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10-3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10-3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10-3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers.

INTRODUCTION: Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood. METHODS: We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. RESULTS: Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. CONCLUSIONS: Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. IMPLICATIONS: Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Late-onset epilepsy predicts stroke: Systematic review and meta-analysis.

OBJECTIVE: Late-onset epilepsy (LOE) is closely associated with cerebrovascular disease, acting as both a marker of cerebrovascular disease (CVD) and occurring as a direct consequence. Despite this, our understanding of LOE as a cerebrovascular phenomenon is in its infancy. LOE also appears to be a harbinger of dementia. METHODS: A systematic review was performed to identify publications relating to LOE and identified observational studies, clinical studies, and radiological studies. RESULTS: A meta-analysis of observational studies demonstrated that patients presenting with LOE experience an increased risk of subsequent stroke (weighted OR 3.88 (95% CI 2.76-5.46)). The additional studies demonstrated clinical and radiological evidence to support the premise that LOE is likely to reflect underlying cerebrovascular disease. SIGNIFICANCE: Cerebrovascular disease risk factors convey increased risk of LOE and LOE can precede stroke and dementia, acting as an early marker for cerebrovascular risk. This may represent a potential point for intervention. There are a number of suggested mechanisms relating LOE to stroke; however, there is limited understanding of the natural history of LOE. Current data support the need for prospective research in order to understand the natural history of LOE and modify disease, in order to reduce the apparent sequelae of stroke and dementia.

Routinely collected patient data in neurology research: a systematic mapping review.

BACKGROUND: This review focuses on neurology research which uses routinely collected data. The number of such studies is growing alongside the expansion of data collection. We aim to gain a broad picture of the scope of how routine healthcare data have been utilised. METHODS: This study follows a systematic mapping review approach which does not make a judgement on the quality of the papers included in the review, thereby enabling a complete overview of the field. RESULTS: Of 4481 publications retrieved, 386 met the eligibility criteria for this study. These publications covered a wide range of conditions, but the majority were based on one or only a small number of neurological conditions. In particular, publications concerned with three discrete areas of neurological practice - multiple sclerosis (MS), epilepsy/seizure and Parkinson's disease - accounted for 60% of the total. MS was the focus of the highest proportion of eligible studies (35%), yet in the recent Global Burden of Neurological Disease study it ranks only 14th out of 15 neurological disorders for DALY rates. In contrast, migraine is the neurological disorder with the highest ranking of DALYs globally (after stroke) and yet it was represented by only 4% of eligible studies. CONCLUSION: This review shows that there is a disproportionately large body of literature pertaining to relatively rare disorders, and a correspondingly small body of literature describing more common conditions. Therefore, there is potential for future research to redress this balance.

Heritability estimates of cortical anatomy: The influence and reliability of different estimation strategies.

Twin study designs have been previously used to investigate the heritability of neuroanatomical measures, such as regional cortical volumes. Volume can be fractionated into surface area and cortical thickness, where both measures are considered to have independent genetic and environmental bases. Region of interest (ROI) and vertex-wise approaches have been used to calculate heritability of cortical thickness and surface area in twin studies. In our study, we estimate heritability using the Human Connectome Project magnetic resonance imaging dataset composed of healthy young twin and non-twin siblings (mean age of 29, sample size of 757). Both ROI and vertex-wise methods were used to compare regional heritability of cortical thickness and surface area. Heritability estimates were controlled for age, sex, and total ipsilateral surface area or mean cortical thickness. In both approaches, heritability estimates of cortical thickness and surface area were lower when accounting for average ipsilateral cortical thickness and total surface area respectively. When comparing both approaches at a regional level, the vertex-wise approach showed higher surface area and lower cortical thickness heritability estimates compared to the ROI approach. The calcarine fissure had the highest surface area heritability estimate (ROI: 44%, vertex-wise: 50%) and posterior cingulate gyrus had the highest cortical thickness heritability (ROI: 50%, vertex-wise 40%). We also observed that limitations in image processing and variability in spatial averaging errors based on regional size may make obtaining true estimates of cortical thickness and surface area challenging in smaller regions. It is important to identify which approach is best suited to estimate heritability based on the research hypothesis and the size of the regions being investigated.

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

APOE-ε4 associates with hippocampal volume, learning, and memory across the spectrum of Alzheimer's disease and dementia with Lewy bodies.

INTRODUCTION: Although the apolipoprotein E ε4-allele (APOE-ε4) is a susceptibility factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored. METHODS: We studied 298 patients (AD = 250, DLB = 48; 38 autopsy-confirmed; NCT01800214) using neuropsychological testing, volumetric magnetic resonance imaging, and APOE genotyping to investigate the association of APOE-ε4 with hippocampal volume and learning/memory phenotypes, irrespective of diagnosis. RESULTS: Across the AD/DLB spectrum: (1) hippocampal volumes were smaller with increasing APOE-ε4 dosage (no genotype × diagnosis interaction observed), (2) learning performance as assessed by total recall scores was associated with hippocampal volumes only among APOE-ε4 carriers, and (3) APOE-ε4 carriers performed worse on long-delay free word recall. DISCUSSION: These findings provide evidence that APOE-ε4 is linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum, which could be useful as biomarkers of disease progression in therapeutic trials of mixed disease.

Heritability of hippocampal subfield volumes using a twin and non-twin siblings design.

The hippocampus is composed of distinct subfields linked to diverse functions and disorders. The subfields can be mapped using high-resolution magnetic resonance images, and their volumes can potentially be used as quantitative phenotypes for genetic investigation of hippocampal function. We estimated the heritability of hippocampus subfield volumes of 465 subjects from the Human Connectome Project (twins and non-twin siblings) using two methods. The first used a univariate model to estimate heritability with and without adjustment for total brain volume (TBV) and ipsilateral hippocampal volume to determine if heritability was uniquely attributable to subfield volume rather than confounds that attributed to global volumes. We observed the right: subiculum, cornu ammonis 2/3, and cornu ammonis 4/dentate gyrus subfields had the highest significant heritability estimates after adjusting for ipsilateral hippocampal volume. In the second analysis, we used a bivariate model to investigate the shared heritability and genetic correlation of the subfield volumes with TBV and ipsilateral hippocampal volume. Genetic correlation demonstrates shared genetic architecture between phenotypes and shared heritability is what proportion of the genetic architecture of one trait is shared by the other. Highest genetic correlations were between subfield volumes and ipsilateral hippocampal volume than with TBV. The pattern was opposite for shared heritability suggesting that subfields share greater proportion of the genetic architecture with TBV than with ipsilateral hippocampal volume. The relationship between the genetic architecture of TBV, hippocampal volume, and of individual subfields should be accounted for when using hippocampal subfield volumes as quantitative phenotypes for imaging genetics studies. Hum Brain Mapp 38:4337-4352, 2017. © 2017 Wiley Periodicals, Inc.

Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.