Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders.

Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Demographic, spatial and temporal dietary intake patterns among 526 774 23andMe research participants.

OBJECTIVE: To characterise dietary habits, their temporal and spatial patterns and associations with BMI in the 23andMe study population. DESIGN: We present a large-scale cross-sectional analysis of self-reported dietary intake data derived from the web-based National Health and Nutrition Examination Survey 2009-2010 dietary screener. Survey-weighted estimates for each food item were characterised by age, sex, race/ethnicity, education and BMI. Temporal patterns were plotted over a 2-year time period, and average consumption for select food items was mapped by state. Finally, dietary intake variables were tested for association with BMI. SETTING: US-based adults 20-85 years of age participating in the 23andMe research programme. PARTICIPANTS: Participants were 23andMe customers who consented to participate in research (n 526 774) and completed web-based surveys on demographic and dietary habits. RESULTS: Survey-weighted estimates show very few participants met federal recommendations for fruit: 2·6 %, vegetables: 5·9 % and dairy intake: 2·8 %. Between 2017 and 2019, fruit, vegetables and milk intake frequency declined, while total dairy remained stable and added sugars increased. Seasonal patterns in reporting were most pronounced for ice cream, chocolate, fruits and vegetables. Dietary habits varied across the USA, with higher intake of sugar and energy dense foods characterising areas with higher average BMI. In multivariate-adjusted models, BMI was directly associated with the intake of processed meat, red meat, dairy and inversely associated with consumption of fruit, vegetables and whole grains. CONCLUSIONS: 23andMe research participants have created an opportunity for rapid, large-scale, real-time nutritional data collection, informing demographic, seasonal and spatial patterns with broad geographical coverage across the USA.

Direct-to-consumer genetic testing companies tell their customers to 'see a genetic counselor'. How do genetic counselors feel about direct-to-consumer genetic testing?

Professional societies, the FDA, and many direct-to-consumer genetic testing (DTC-GT) companies have highlighted the value of counseling from a medical professional with genetics expertise in order to enhance the value and minimize the risks associated with DTC-GT. However, there is limited information available identifying genetic counselors' own views on DTC-GT, their willingness to counsel consumers based on DTC-GT results, and their experiences to date seeing DTC-GT consumers in a clinical setting. We surveyed genetic counselors accessed through mailing lists associated with the National Society of Genetic Counselors (NSGC) and the American Board of Genetic Counseling (ABGC). Response rate was estimated to be 12.2% (n = 482). A majority of all respondents (56.4%, n = 263) described themselves as feeling negatively or very negatively toward DTC-GT; only 6.9% (n = 32) described themselves as feeling positively or very positively. While 90.9% of respondents (n = 398) believed that DTC-GT would be improved with the involvement of genetic counselors, only 31.2% agreed or strongly agreed that they are comfortable providing counseling to DTC-GT consumers (n = 142). Clinical counseling of DTC-GT consumers is not routine but it is also not uncommon; 40.1% of all respondents (n = 189) have seen at least one consumer in clinic for the sole purpose of reviewing DTC-GT results. The results of our study suggest that most respondents would be more accepting of DTC-GT if genetic counseling was a part of the process, but the majority of counselors do not feel comfortable providing this service.

Unhealthy Behaviours and Risk of Parkinson's Disease: A Mendelian Randomisation Study.

BACKGROUND: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. OBJECTIVE: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. METHODS: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. RESULTS: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. CONCLUSION: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

The Impact of Direct-to-Consumer Genetic Testing on Patient and Provider.

Direct-to-consumer genetic testing came on the scene 2 decades ago as a means for allowing consumers to access their genetic information without the involvement of a physician or genetic counselor. Results are delivered directly to the consumer, often leading to misinterpretation and needless medical interventions or false reassurance. Increasingly, we are seeing these patients in our genetics clinics for test interpretation, management guidance and confirmatory genetic testing.

Clinical utility of microarrays: current status, existing challenges and future outlook.

Microarray-based clinical tests have become powerful tools in the diagnosis and treatment of diseases. In contrast to traditional DNA-based tests that largely focus on single genes associated with rare conditions, microarray-based tests are ideal for the study of diseases with underlying complex genetic causes. Several microarray based tests have been translated into clinical practice such as MammaPrint and AmpliChip CYP450. Additional cancer-related microarray-based tests are either in the process of FDA review or under active development, including Tissue of Tumor Origin and AmpliChip p53. All diagnostic microarray testing is ordered by physicians and tested by a Clinical Laboratories Improvement Amendment-certified (CLIA) reference laboratory. Recently, companies offering consumer based microarray testing have emerged. Individuals can order tests online and service providers deliver the results directly to the clients via a password-protected secure website. Navigenics, 23andMe and deCODE Genetics represent pioneering companies in this field. Although the progress of these microarray-based tests is extremely encouraging with the potential to revolutionize the recognition and treatment of common diseases, these tests are still in their infancy and face technical, clinical and marketing challenges. In this article, we review microarray-based tests which are currently approved or under review by the FDA, as well as the consumer-based testing. We also provide a summary of the challenges and strategic solutions in the development and clinical use of the microarray-based tests. Finally, we present a brief outlook for the future of microarray-based clinical applications.

"The Google of Healthcare": enabling the privatization of genetic bio/databanking.

PURPOSE: 23andMe is back on the market as the first direct-to-consumer genetic testing company that "includes reports that meet Food and Drug Administration (FDA) standards…." But, whereas its front-end product is selling individual genetic tests online, its back-end business model is amassing one of the largest privately owned genetic databases in the world. What is the effect, however, of the private control of bio/databases on genetic epidemiology and public health research? METHODS: The recent federal government notices of proposed rulemaking for: (1) revisions to regulations governing human subjects research and (2) whether certain direct-to-consumer genetic tests should require premarket FDA review, were reviewed and related to the 23andMe product, business model, and consumer agreements. RESULTS: FDA regulatory action so far has focused on the return of consumer test reports but it should also consider the broader misuse of data and information not otherwise protected by human subjects research regulations. CONCLUSIONS: As the federal government revises its decades-old human subjects research structure, the Executive Office of the President (EOP) should consider a cohesive approach to regulating private genetic bio/databanks. This strategy should allow the FDA and other agencies to play a role in expanding current regulatory coverage.

The Googlization of health research: from disruptive innovation to disruptive ethics.

Consumer-oriented mobile technologies offer new ways of capturing multidimensional health data, and are increasingly seen as facilitators of medical research. This has opened the way for large consumer tech companies, like Apple, Google, Amazon and Facebook, to enter the space of health research, offering new methods for collecting, storing and analyzing health data. While these developments are often portrayed as 'disrupting' research in beneficial ways, they also raise many ethical issues. These can be organized into three clusters: questions concerning the quality of research; privacy/informed consent; and new power asymmetries based on access to data and control over technological infrastructures. I argue that this last cluster, insofar as it may affect future research agendas, deserves more critical attention.

When consumers get their genomes.

Direct-to-consumer (DTC) genomics services enable consumers to gain access to their DNA sequence using research microarrays and curated genetic association literature. For a few hundred US dollars, consumers can compare their genotypes against current research results, including risk estimates for common diseases based on SNPs. The DTC companies are legally avoiding claims of medical utility but are assembling the components needed for genomic-based healthcare. They represent an early vision of what modern personalized medicine could become. This has resulted in some conflict between the research and regulatory communities and there are reasonable questions as to whether the science is sufficiently mature. The DTC providers are exploring and solving problems associated with communicating complex scientific data and have the potential to revolutionize research by organizing large communities efficiently using web technology.