Genetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank.

The causes of temporal fluctuations in adult traits are poorly understood. Here, we investigate the genetic determinants of within-person trait variability of 8 repeatedly measured anthropometric traits in 50,117 individuals from the UK Biobank. We found that within-person (non-directional) variability had a SNP-based heritability of 2-5% for height, sitting height, body mass index (BMI) and weight (P ≤ 2.4 × 10-3). We also analysed longitudinal trait change and show a loss of both average height and weight beyond about 70 years of age. A variant tracking the Alzheimer's risk APOE- E 4 allele (rs429358) was significantly associated with weight loss ( ß = -0.047 kg per yr, s.e. 0.007, P = 2.2 × 10-11), and using 2-sample Mendelian Randomisation we detected a relationship consistent with causality between decreased lumbar spine bone mineral density and height loss (bxy = 0.011, s.e. 0.003, P = 3.5 × 10-4). Finally, population-level variance quantitative trait loci (vQTL) were consistent with within-person variability for several traits, indicating an overlap between trait variability assessed at the population or individual level. Our findings help elucidate the genetic influence on trait-change within an individual and highlight disease risks associated with these changes.

Brain cell-type shifts in Alzheimer's disease, autism, and schizophrenia interrogated using methylomics and genetics.

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer's disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders.

Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D.

Vitamin D status-a complex trait influenced by environmental and genetic factors-is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)-the main circulating form of vitamin D-in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D.

Visit and Between-Visit Interaction Frequency Before and After COVID-19 Telehealth Implementation.

Importance: Telehealth implementation associated with the COVID-19 public health emergency (PHE) affected patient-clinical team interactions in numerous ways. Yet, studies have narrowly examined billed patient-clinician visits rather than including visits with other team members (eg, pharmacists) or between-visit interactions. Objective: To evaluate rates of change over time in visits (in-person, telehealth) and between-visit interactions (telephone calls, patient portal messages) overall and by key patient characteristics. Design, Setting, and Participants: This retrospective cohort study included adults with diabetes receiving primary care at urban academic (University of California San Francisco [UCSF]) and safety-net (San Francisco Health Network [SFHN]) health care systems. Encounters from April 2019 to March 2021 were analyzed. Exposure: Telehealth implementation over 3 periods: pre-PHE (April 2019 to March 2020), strict shelter-in-place (April to June 2020), and hybrid-PHE (July 2020 to March 2021). Main Outcomes and Measures: The main outcomes were rates of change in monthly mean number of total encounters, visits with any health care team member, visits with billing clinicians, and between-visit interactions. Key patient-level characteristics were age, race and ethnicity, language, and neighborhood socioeconomic status (nSES). Results: Of 15 148 patients (4976 UCSF; 8975 SFHN) included, 2464 (16%) were 75 years or older, 7734 (51%) were female patients, 9823 (65%) self-identified as racially or ethnically minoritized, 6223 (41%) had a non-English language preference, and 4618 (31%) lived in the lowest nSES quintile. After accounting for changes to care delivery through an interrupted time-series analysis, total encounters increased in the hybrid-PHE period (UCSF: 2.3% per patient/mo; 95% CI, 1.6%-2.9% per patient/mo; SFHN: 1.8% per patient/mo, 95% CI, 1.3%-2.2% per patient/mo), associated primarily with growth in between-visit interactions (UCSF: 3.1% per patient/mo, 95% CI, 2.3%-3.8% per patient/mo; SFHN: 2.9% per patient/mo, 95% CI, 2.3%-3.4% per patient/mo). In contrast, rates of visits were stable during the hybrid-PHE period. Although there were fewer differences in visit use by key patient-level characteristics during the hybrid-PHE period, pre-PHE differences in between-visit interactions persisted during the hybrid-PHE period at SFHN. Asian and Chinese-speaking patients at SFHN had fewer monthly mean between-visit interactions compared with White patients (0.46 [95% CI, 0.42-0.50] vs 0.59 [95% CI, 0.53-0.66] between-visit interactions/patient/mo; P < .001) and English-speaking patients (0.52 [95% CI, 0.47-0.58] vs 0.61 [95% CI, 0.56-0.66] between-visit interactions/patient/mo; P = .03). Conclusions and Relevance: In this study, pre-PHE growth in overall patient-clinician encounters persisted after PHE-related telehealth implementation, driven in both periods by between-visit interactions. Differential utilization based on patient characteristics was observed, which may indicate disparities. The implications for health care team workload and patient outcomes are unknown, particularly regarding between-visit interactions. Therefore, to comprehensively understand care utilization for patients with chronic diseases, research should expand beyond billed visits.

HIV viral load testing and monitoring in Côte d'Ivoire: A survival analysis of viral load testing and suppression, and evaluation of adherence to national recommendations.

Routine viral load (VL) monitoring is the standard of care in Côte d'Ivoire and allows for effective treatment guidance for people living with human immunodeficiency virus (HIV) to reach viral load suppression (VLS). For VL monitoring to be effective in reducing the impact of HIV, it must be provided in accordance with national guidance. This study aimed to evaluate VL testing, VLS rates and adherence to national guidance for VL testing using data collected from three national laboratories. We collected data on VL testing between 2015-2018 from OpenELIS (OE), an open-source electronic laboratory information system. We merged data by unique patient ID for patients (0-80 years old) who received multiple VL tests to calculate time between tests. We defined VLS as HIV RNA ≤1,000 copies/mL based on Côte d'Ivoire national and WHO guidance at the time of data collection. We used the Kaplan-Meier survival estimator to estimate time between ART (antiretroviral therapy) initiation and the first VL test, time between subsequent VL tests, and to estimate the proportion of people living with HIV (PLHIV) who were virally suppressed within 12 months of ART initiation. At the first documented VL test, 79.6% of patients were virally suppressed (95% CI: 78.9-80.3). Children under 15 were the least likely to be virally suppressed (55.2%, 95% CI: 51.5-58.8). The median time from ART initiation to the first VL sample collection for testing was 7.8 months (IQR:6.2-13.4). 72.4% of patients were virally suppressed within one year of treatment initiation (95% CI:71.5-73.3). Approximately 30% of patients received a second VL test during the 4-year study period. The median time between the first and second VL tests was 24.9 months (IQR: 4.7->40). Most PLHIV received their first VL test within the recommended 12 months of ART initiation but did not receive subsequent VL monitoring tests within the recommended time frame, reducing the benefits of VL monitoring. While VLS was fairly high, children were least likely to be virally suppressed. Our findings highlight the importance of regular VL monitoring after the first VL test, especially for children.

Social Determinants of Health Documentation in Structured and Unstructured Clinical Data of Patients With Diabetes: Comparative Analysis.

Background: Electronic health records (EHRs) have yet to fully capture social determinants of health (SDOH) due to challenges such as nonexistent or inconsistent data capture tools across clinics, lack of time, and the burden of extra steps for the clinician. However, patient clinical notes (unstructured data) may be a better source of patient-related SDOH information. Objective: It is unclear how accurately EHR data reflect patients' lived experience of SDOH. The manual process of retrieving SDOH information from clinical notes is time-consuming and not feasible. We leveraged two high-throughput tools to identify SDOH mappings to structured and unstructured patient data: PatientExploreR and Electronic Medical Record Search Engine (EMERSE). Methods: We included adult patients (≥18 years of age) receiving primary care for their diabetes at the University of California, San Francisco (UCSF), from January 1, 2018, to December 31, 2019. We used expert raters to develop a corpus using SDOH in the compendium as a knowledge base as targets for the natural language processing (NLP) text string mapping to find string stems, roots, and syntactic similarities in the clinical notes of patients with diabetes. We applied advanced built-in EMERSE NLP query parsers implemented with JavaCC. Results: We included 4283 adult patients receiving primary care for diabetes at UCSF. Our study revealed that SDOH may be more significant in the lives of patients with diabetes than is evident from structured data recorded on EHRs. With the application of EMERSE NLP rules, we uncovered additional information from patient clinical notes on problems related to social connectionsisolation, employment, financial insecurity, housing insecurity, food insecurity, education, and stress. Conclusions: We discovered more patient information related to SDOH in unstructured data than in structured data. The application of this technique and further investment in similar user-friendly tools and infrastructure to extract SDOH information from unstructured data may help to identify the range of social conditions that influence patients' disease experiences and inform clinical decision-making.

Neighborhood-level COVID vaccination and booster disparities: A population-level analysis across California.

Objectives: To describe vaccine and booster uptake by neighborhood-level factors in California. Methods: We examined trends in COVID-19 vaccination up to September 21, 2021, and boosters up to March 29, 2022 using data from the California Department of Public Health. Quasi-Poisson regression was used to model the association between neighborhood-level factors and fully vaccinated and boosted among ZIP codes. Sub-analyses on booster rates were compared among the 10 census regions. Results: In a minimally adjusted model, a higher proportion of Black residents was associated with lower vaccination (HR = 0.97; 95%CI: 0.96-0.98). However, in a fully adjusted model, proportion of Black, Hispanic/Latinx, and Asian residents were associated with higher vaccination rates (HR = 1.02; 95%CI: 1.01-1.03 for all). The strongest predictor of low vaccine coverage was disability (HR = 0.89; 95%CI: 0.86-0.91). Similar trends persisted for booster doses. Factors associated with booster coverage varied by region. Conclusions: Examining neighborhood-level factors associated with COVID-19 vaccination and booster rates uncovered significant variation within the large and geographically and demographically diverse state of California. Equity-based approaches to vaccination must ensure a robust consideration of multiple social determinants of health.

Impacts of Individual Patient Language and Neighborhood Ethnic Enclave on COVID-19 Test Positivity Among Hispanic/Latinx Patients in San Francisco.

BACKGROUND: Given the known disparities in COVID-19 within the Hispanic/Latinx community, we sought to examine the interaction between individual-level and neighborhood-level social determinants of health using linked electronic health record data. METHODS: We examined electronic health record data linked to neighborhood data among Hispanic/Latinx patients tested for COVID-19 between March 1, 2020, and February 28, 2021, from 2 large health care systems in San Francisco. Hispanic/Latinx ethnic enclave is measured using an index of census-tract level indicators of ethnicity, nativity, and language. Multilevel logistic regression models examined associations between ethnic enclave and COVID-19 positivity (COVID-19+), adjusting for patient-level sociodemographic and clinical characteristics and health system. Cross-level interactions were used to test whether associations between ethnic enclave and COVID-19+ differed by patient language preference. RESULTS: Among 26,871 patients, mean age was 37 years, 56% had Spanish-language preference, and 21% were COVID-19+. In unadjusted models, patients living in the highest versus lowest Hispanic/Latinx enclave had 3.2 higher odds of COVID-19+ (95% CI, 2.45-4.24). Adjusted, the relationship between ethnic enclave and COVID-19+ was attenuated, but not eliminated (odds ratio: 1.4; 95% CI, 1.13-1.17). Our results demonstrated a significant cross-level interaction, such that the influence of ethnic enclave was modified by patient language preference. For individuals with Spanish-language preference, risk of COVID-19+ was high regardless of neighborhood context, whereas for those with English preference, neighborhood ethnic enclave more than doubled the odds of infection. CONCLUSIONS: Findings suggest that a multilevel and intersectional approach to the study of COVID-19 inequities may illuminate dimensions of health inequity that affect marginalized communities and offer insights for targeted clinical and community-based interventions.

Parsimonious model for mass-univariate vertexwise analysis.

Purpose: Covariance between gray-matter measurements can reflect structural or functional brain networks though it has also been shown to be influenced by confounding factors (e.g., age, head size, and scanner), which could lead to lower mapping precision (increased size of associated clusters) and create distal false positives associations in mass-univariate vertexwise analyses. Approach: We evaluated this concern by performing state-of-the-art mass-univariate analyses (general linear model, GLM) on traits simulated from real vertex-wise gray matter data (including cortical and subcortical thickness and surface area). We contrasted the results with those from linear mixed models (LMMs), which have been shown to overcome similar issues in omics association studies. Results: We showed that when performed on a large sample ( N = 8662 , UK Biobank), GLMs yielded greatly inflated false positive rate (cluster false discovery rate > 0.6 ). We showed that LMMs resulted in more parsimonious results: smaller clusters and reduced false positive rate but at a cost of increased computation. Next, we performed mass-univariate association analyses on five real UKB traits (age, sex, BMI, fluid intelligence, and smoking status) and LMM yielded fewer and more localized associations. We identified 19 significant clusters displaying small associations with age, sex, and BMI, which suggest a complex architecture of at least dozens of associated areas with those phenotypes. Conclusions: The published literature could contain a large proportion of redundant (possibly confounded) associations that are largely prevented using LMMs. The parsimony of LMMs results from controlling for the joint effect of all vertices, which prevents local and distal redundant associations from reaching significance.

The association between health workforce availability and HIV-program outcomes in Côte d'Ivoire.

OBJECTIVE: The purpose of this study was to assess the distribution of HIV-program staff and the extent to which their availability influences HIV programmatic and patient outcomes. METHODS: The study was a facility level cross-sectional survey. Data from October 2018 to September 2019 were abstracted from HIV program reports conducted in 18 districts of Côte d'Ivoire. The distribution of staff in clinical, laboratory, pharmacy, management, lay, and support cadres were described across high and low antiretroviral therapy (ART) volume facilities. Non-parametric regression was used to estimate the effects of cadre categories on the number of new HIV cases identified, the number of cases initiated on ART, and the proportion of patients achieving viral load suppression. RESULTS: Data from 49,871 patients treated at 216 health facilities were included. Low ART volume facilities had a median of 8.1 staff-per-100 ART patients, significantly higher than the 4.4 staff-per-100 ART patients at high-ART volume facilities. One additional laboratory staff member was associated with 4.30 (IQR: 2.00-7.48, p < 0.001) more HIV cases identified and 3.81 (interquartile range [IQR]: 1.44-6.94, p < 0.001) additional cases initiated on ART. Similarly, one additional lay worker was associated with 2.33 (IQR: 1.00-3.43, p < 0.001) new cases identified and 2.24 (IQR: 1.00-3.31, p < 0.001) new cases initiated on ART. No cadres were associated with viral suppression. CONCLUSIONS: HCWs in the laboratory and lay cadre categories were associated with an increase in HIV-positive case identification and initiation on ART. Our findings suggest that allocation of HCWs across health facilities should take into consideration the ART patient volume. Overall, increasing investment in health workforce is critical to achieve national HIV goals and reaching HIV epidemic control.

Correlates of cervical cancer screening among women living with HIV in Kenya: A cross-sectional study.

OBJECTIVE: Cervical cancer is the leading cause of cancer-related death among Kenyan women. It is important to identify how demographics and knowledge of cervical cancer are associated with screening to determine best practices for targeted screening efforts. METHODS: We conducted a sub-analysis of women who were asked about cervical cancer from a cross-sectional study of women attending large HIV care and treatment programs across Kenya between June and September 2016. RESULTS: 1671 of 3007 (56%) women reported ever being screened, 804 (48%) of whom were screened within the last 12 months. Prevalence of screening was highest among women who were older (adjusted prevalence ratio [APR] age 35-49 vs. 18-24: 2.26, 95% CI: 1.68-3.05, P < 0.001), employed (APR: 1.55, 95% CI: 1.24-1.93, P < 0.001), married (APR: 1.27, 95% CI: 1.01-1.59, P = 0.047), had at least secondary education (APR: 1.45, 95% CI: 1.19-1.77, P < 0.001), with longer time since HIV diagnosis (APR: 1.09/year average increase, 95% CI: 1.04-1.13, P < 0.001). 36% knew cervical cancer is treatable. CONCLUSION: Characteristics linked to social or economic capital are correlated with cervical cancer screening. Integrating cervical cancer screening into HIV care and educating patients on the need for annual screening and potential treatment are important strategies for increasing screening uptake.

Phenotypic covariance across the entire spectrum of relatedness for 86 billion pairs of individuals.

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.

Widespread signatures of natural selection across human complex traits and functional genomic categories.

Understanding how natural selection has shaped genetic architecture of complex traits is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level GWAS data to estimate multiple genetic architecture parameters including selection signature. Here, we present a method (SBayesS) that only requires GWAS summary statistics. We analyse data for 155 complex traits (n = 27k-547k) and project the estimates onto those obtained from evolutionary simulations. We estimate that, on average across traits, about 1% of human genome sequence are mutational targets with a mean selection coefficient of ~0.001. Common diseases, on average, show a smaller number of mutational targets and have been under stronger selection, compared to other traits. SBayesS analyses incorporating functional annotations reveal that selection signatures vary across genomic regions, among which coding regions have the strongest selection signature and are enriched for both the number of associated variants and the magnitude of effect sizes.

Genetic control of temperament traits across species: association of autism spectrum disorder risk genes with cattle temperament.

BACKGROUND: Temperament traits are of high importance across species. In humans, temperament or personality traits correlate with psychological traits and psychiatric disorders. In cattle, they impact animal welfare, product quality and human safety, and are therefore of direct commercial importance. We hypothesized that genetic factors that contribute to variation in temperament among individuals within a species will be shared between humans and cattle. Using imputed whole-genome sequence data from 9223 beef cattle from three cohorts, a series of genome-wide association studies was undertaken on cattle flight time, a temperament phenotype measured as the time taken for an animal to cover a short-fixed distance after release from an enclosure. We also investigated the association of cattle temperament with polymorphisms in bovine orthologs of risk genes for neuroticism, schizophrenia, autism spectrum disorders (ASD), and developmental delay disorders in humans. RESULTS: Variants with the strongest associations were located in the bovine orthologous region that is involved in several behavioural and cognitive disorders in humans. These variants were also partially validated in independent cattle cohorts. Genes in these regions (BARHL2, NDN, SNRPN, MAGEL2, ABCA12, KIFAP3, TOPAZ1, FZD3, UBE3A, and GABRA5) were enriched for the GO term neuron migration and were differentially expressed in brain and pituitary tissues in humans. Moreover, variants within 100 kb of ASD susceptibility genes were associated with cattle temperament and explained 6.5% of the total additive genetic variance in the largest cattle cohort. The ASD genes with the most significant associations were GABRB3 and CUL3. Using the same 100 kb window, a weak association was found with polymorphisms in schizophrenia risk genes and no association with polymorphisms in neuroticism and developmental delay disorders risk genes. CONCLUSIONS: Our analysis showed that genes identified in a meta-analysis of cattle temperament contribute to neuron development functions and are differentially expressed in human brain tissues. Furthermore, some ASD susceptibility genes are associated with cattle temperament. These findings provide evidence that genetic control of temperament might be shared between humans and cattle and highlight the potential for future analyses to leverage results between species.

A unified framework for association and prediction from vertex-wise grey-matter structure.

The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.

Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration.

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study.

Genome-wide association study of dietary intake in the UK biobank study and its associations with schizophrenia and other traits.

Motivated by observational studies that report associations between schizophrenia and traits, such as poor diet, increased body mass index and metabolic disease, we investigated the genetic contribution to dietary intake in a sample of 335,576 individuals from the UK Biobank study. A principal component analysis applied to diet question item responses generated two components: Diet Component 1 (DC1) represented a meat-related diet and Diet Component 2 (DC2) a fish and plant-related diet. Genome-wide association analysis identified 29 independent single-nucleotide polymorphisms (SNPs) associated with DC1 and 63 SNPs with DC2. Estimated from over 35,000 3rd-degree relative pairs that are unlikely to share close family environments, heritabilities for both DC1 and DC2 were 0.16 (standard error (s.e.) = 0.05). SNP-based heritability was 0.06 (s.e. = 0.003) for DC1 and 0.08 (s.e = 0.004) for DC2. We estimated significant genetic correlations between both DCs and schizophrenia, and several other traits. Mendelian randomisation analyses indicated a negative uni-directional relationship between liability to schizophrenia and tendency towards selecting a meat-based diet (which could be direct or via unidentified correlated variables), but a bi-directional relationship between liability to schizophrenia and tendency towards selecting a fish and plant-based diet consistent with genetic pleiotropy.

Improved polygenic prediction by Bayesian multiple regression on summary statistics.

Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R2 by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.

A resource-efficient tool for mixed model association analysis of large-scale data.

The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB.