Patient-reported drug responses offer an alternative approach to design and develop a predictive model for treatment-resistant depression (TRD) in major depressive disorder (MDD). The variables described in phenotypic analysis (i.e., demographics, depression clinical characteristics, psychiatric comorbidities, and vulnerability characteristics) of the antidepressant efficacy survey from previously reported study among 23andMe, Inc. research participants were identified as predictors to classify TRD or non-TRD. A total of 101 features were engineered for 23,779 participants, with stratified split between training (80% of the total participants included in the model) and holdout (20% of the participants) datasets. Significant predictors included residual symptoms, years in life having ≥ 2 weeks depressive episode, stress level, duration of depressive episodes, age, suicidal ideation, symptoms of post-traumatic stress disorder, and latency. The final model achieved a model performance with receiver operating characteristics area under curve (AUC) at 78% and precision recall AUC at 44%. The proposed predictive model could improve the management of MDD by providing an assessment of risk factors and antidepressant treatment effects, thereby facilitating reliable identification of patients with TRD. The model could potentially address the gaps observed in real-world settings, where identification of TRD is often delayed.

There is increasing evidence that the methyl-binding domain (MBD) is a protein-protein interaction motif that can function independently of methylated DNA binding. The MBD proteins found throughout plants and invertebrates duplicated into multiple vertebrate DNA and non-DNA-binding members (MBD1, MBD2, MBD3, MBD4, MBD5, MBD6, MECP2, BAZ2A, BAZ2B, SETDB1, and SETDB2). Although many invertebrate species possess MBD proteins that can bind and recognize DNA methylation, the DNA-binding function has been independently lost multiple times, with only minor alterations to the protein interaction residues. The nucleosome remodeling and deacetylase (NuRD) complex, which interacts with MBD2/3 and is colocalized with MBD1/4 ChIP-Seq, is maintained in species where MBD2/3 cannot bind to DNA. NuRD ChIP-seq data from HepG2 cell line, human induced pluripotent stem cells (iPSCs), and human iPSC-derived liver cells suggest that the NuRD complex is highly localized to nonmethylated CpG-rich housekeeping gene promoter elements, which are essential in organogenesis and maintained within the Drosophila melanogaster MBD2/3 non-DNA-binding system. Integration of MBD interaction proteins and NuRD gene expression from >115 million cells of single-cell RNA-seq, along with thousands of bulk tissue profiles, highlights a critical role of MBD3, MECP2, and GATAD2B in brain development and intellectual disability syndromes that is maintained throughout invertebrate neural development and likely involves evolutionary expanded entanglement as the vertebrate MBD proteins expanded. This work suggests that MBD has a largely unexplored role as a critical protein interaction motif that is evolutionarily conserved for regulating enhancers and promoters.NEW & NOTEWORTHY The evolution of the methyl-binding domain (MBD) suggests a shared function in gene regulation, from plants to humans, with the conservation of non-DNA-interacting amino acids critical for protein-protein interactions. The MBD-regulated NuRD complex localizes to promoters of housekeeping genes with hypomethylated CpG islands. Expression profiles suggest a shared role for NuRD complex components in neurodevelopment, where the MBD3 and GATAD2B subcomplex of NuRD may be underexplored due to its non-DNA-binding biology.

OBJECTIVE:To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms. METHODS:We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms according to genetic exposure. RESULTS:By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status. INTERPRETATION:Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

Background: Lipoprotein(a) (Lp[a]) is a circulating plasma lipoprotein that is emerging as an important independent risk factor for vascular disease. Lp(a) levels are 75-90% heritable, predominantly determined by copy number variation and single nucleotide polymorphisms (SNPs) at the LPA gene. Methods: Using ~370K individuals with serum measurements of Lp(a) in the UK Biobank European cohort, we constructed a genetic risk score (GRS) consisting of 29 SNPs in the vicinity of LPA which explained 68.18% of variation in Lp(a). Using the LPA GRS to instrument Lp(a), we conducted phenome-wide Mendelian randomization analysis (MR-PheWAS) across a spectrum of 489 medically-relevant phenotypes in ~7.3M individuals from the 23andMe, Inc. database, and compared effects to those derived from a GRS for low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Through multivariable MR, we sought to assess the direct causal effect of Lp(a) on cardiovascular disease risks while keeping LDL-C or apoB constant. Results: MR-PheWAS confirmed previously reported Lp(a) causal effects on coronary artery disease (CAD: OR = 1.199, 95% CI = [1.193, 1.205], p-value < 2.23e-308, for every 59.632 nmol/L higher Lp(a) instrumented by the LPA GRS), and revealed additional genetically-predicted effects largely confined to cardiovascular endpoints, including a novel effect for restrictive cardiomyopathy (OR = 1.101, 95% CI = [1.068, 1.134], p-value = 3e-10). We scaled the LPA, LDL-C and apoB GRS such that they each had the same OR for MACE (major adverse cardiovascular events). Using the scaling rubric, similar magnitudes of effect were seen for the three lipid traits for most vascular diseases, with the exception of peripheral artery disease, aortic stenosis and dilated cardiomyopathy, where Lp(a) had larger genetically-predicted effect sizes compared to LDL-C and apoB. Multivariable MR identified Lp(a) to retain a causal effect on MACE while accounting for LDL-C or apoB. To achieve the 25% relative risk reduction in major vascular events, as seen with a 1 mmol/L reduction in LDL-C from statin trials, we anticipate that Lp(a) ought to be reduced by ~ 90 mg/dL (200 nmol/L), highlighting the importance of not only using therapies that have a profound impact on Lp(a) lowering, but also selecting individuals that have high Lp(a) concentrations at baseline. Conclusion: Lp(a) has genetically-predicted causal effects on a broad range of cardiovascular diseases beyond CAD, with minimal effects seen for non-vascular disease. ### Competing Interest Statement All authors are employed by and hold stock or stock options in 23andMe, Inc. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Eligible research participants were selected from the 23andMe customer base who provided informed consent to participate in the research online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent Review Services (E&I Review, now Salus IRB). Inclusion criteria of the research participants was based on their consent status at the time when the data analysis was initiated. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson’s disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A sub-stantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 pheno-types. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

Importance: The lack of information on progression, phenoconversion, and risk of dementia in a large genotyped sample impedes reliable enrichment for early interventional trials in Parkinson's disease (PD). Objective: To investigate PD penetrance, risk, motor/non-motor phenotypes, and APOE allele effects in LRRK2 G2019S and GBA N370S carriers. Design: Observational longitudinal case-control self-report survey study. Setting: A US population-based study cohort enrolled in the 23andMe, Inc. and Fox Insight Genetic Substudy (FIGS) databases. Participants: The total cohort included 7,586,842 participants (n=35,163 PD; 27% of PD cases from FIGS); 8,791 LRRK2 G2019S carriers (565 with PD), 37,427 GBA N370S carriers (524 with PD), 244 dual carriers (37 with PD), and 7.5 million non-carriers (34,037 with PD). Exposure(s): LRRK2 G2019S, GBA N370S, APOE E2/E3/E4 alleles and PD polygenic risk scores (PRS). Main Outcome(s) and Measure(s): Cumulative incidence of PD was estimated using Kaplan-Meier and accelerated failure time models. Relative odds of developing motor and non-motor symptoms were calculated using logistic regression models according to genetic exposure. Impact of the APOE alleles was estimated in a dose-dependent analysis. Results: By the age of 80 years, the cumulative incidence of PD was 43% for dual carriers, 32% for LRRK2 G2019S carriers, 6% for GBA N370S carriers, and 3% for non-carriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. Motor symptoms were similar in LRRK2 G2019S, GBA N370S, and non-carriers with PD. GBA N370S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 G2019S the lowest. APOE E4 dosage was associated with greater odds of developing hallucinations and cognitive decline in addition to carrier status. Conclusions and Relevance: Our findings support the use of genetic screening--including LRRK2 G2019S, GBA N370S, APOE E4, and PRS--to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetic risk factors. ### Competing Interest Statement At the time of their contributions, the following authors were employed by and/or held stock or stock options in 23andMe, Inc.: MJK, MVH, PF, JS, AG, ST, KS, DAH, JYT, SA, LNK. ### Funding Statement This study was funded by The Michael J. Fox Foundation for Parkinson's Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 23andMe research participants provided informed consent and volunteered to participate in the research online, under a protocol approved by Ethical & Independent (E&I) Review Services--an external IRB that is accredited by the Association for Accreditation of Human Research Protection Programs. As of 2022, E&I Review Services is part of Salus IRB (https://www.versiticlinicaltrials.org/salusirb). Fox Insight Genetic Substudy (FIGS) participants were 18 years or older and provided informed consent via the Fox Insight website (WCG IRB IRB#: 120160179, Legacy IRB#: 14-236, Sponsor Protocol Number: 1, Study Title: Fox Insight) (Gottesman et al., 2024). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Model outputs for all logistic regressions and survival models are provided as eTables. Individual-level data from 23andMe are not publicly available due to participant confidentiality and in accordance with the IRB-approved protocol under which the study was conducted. The Fox Insight Genetic Substudy participant data are available through Fox DEN (https://foxden.michaeljfox.org). No custom code or software was generated as part of the study. Details of all software packages used for data processing and analysis may be found in the "Methods" section.

To conduct a prospective longitudinal observational study of LRRK2 G0219S carriers and non-carriers with and without Parkinson disease (PD).

Understanding factors related to treatment response is of paramount importance for improving patient outcomes and reducing socio-economic burdens on healthcare systems. Dissecting the etiology of treatment related outcomes is challenging because, in addition to compound specific pharmacodynamics and pharmacokinetics, perceived and realized treatment efficacy is a complex function of treatment compliance, healthcare access and literacy, diagnostic accuracy, and etiology heterogeneity. As such, previous research is limited by small sample sizes and narrowly defined treatment outcomes that we address with unique data and a broad analysis approach. The Affective disorders, Environment, and Cognitive Trait (AFFECT) study is a longitudinal study of 23 and Me customers who self-reported major depression (MDD, n=14,768) or bipolar disorder (BPD, n=9,864)5. Participants were genotyped and administered multiple remote assessments of treatment outcomes. We defined multiple treatment outcomes from self-report of use, response to, and cessation of specific medications. For each, we performed Genome-wide associations study (GWAS), estimated SNP-heritability and genetic correlations, and applied multiple polygenic score (PGS) profile analysis. MDD and BPD PGS were not the strongest predictors (across tests: min p=9.20e-08, mean chi-sq=4.98), with educational attainment and socio-behavioral PGS more strongly associated (min p = 2.48e-38, mean chi-sq=7.62). The strongest genetic associations were with antipsychotic use in affective disorders, with those indicating use having significantly higher PGS for ADHD (beta=0.1226, s.e.=0.0169, p=3.82e-13), MDD (beta=0.0801, s.e.=0.0168, p=1.94e-06), Neuroticism (beta=0.0956, s.e.=0.0168, p=1.28e-08), perceived lack of Social Support (beta=0.0678, s.e.=0.0168, p=5.59e-05) and exercise (beta=0.0983, s.e.=0.0168, p=5.02e-09), and significantly lower PGS for educational attainment (beta=-0.2253, s.e.=0.0174, p=2.48e-38). GWAS yielded seven genome-wide significant loci, including 1 for antipsychotic use and 4 for inferred treatment resistance. FUMA and literature search of genes within these loci suggest a number of plausible candidates with previous connections psychiatric disorders (e.g., PTPRT, SEL1L), interactions with relevant medications (e.g. ADCY8, CDH7), and expression in the brain (e.g. PTPRT, STON2). Our broad approach systematically defined multiple treatment outcomes from self-reported survey data to identify individual loci and polygenic scores associated with treatment related outcomes. We highlight two broad themes, that, utilization of antipsychotic medication in affective disorders is a strong indicator of patient genetic profile and that studies defining treatment resistance by drug switches should carefully attend to genetic heterogeneity in intermediate outcomes. We hope future work can replicate and extend these findings.

This study investigated burden of 'not well-controlled' asthma, overall and by Global Initiative for Asthma (GINA) Step, among treated asthma patients in Practice Fusion's research database. Asthma control (Asthma Control Test [ACT]) was stratified by GINA Step; prevalence ratios were estimated using Poisson regression with robust variance controlled for confounders. ACT scores ≤19 reflect not well-controlled; >19 reflect 'well-controlled' asthma. Of 15,579 patients, 30% had not well-controlled asthma at index date. The proportion of patients with not well-controlled asthma increased from GINA Step 1 (29%) to Step 5 (45%). Compared with Step 1, the proportion of patients with not well-controlled asthma was 0.87-times lower in Step 2, 1.10-times greater in Step 4, and 1.37-times greater in Step 5. Results suggest that despite available treatments, patients remain symptomatic across GINA Steps in real-world primary care and specialist outpatient practices, with incremental disease burden and unmet medical need in these populations.

Background Human genetics provides opportunities for enhancing disease prediction through polygenic risk scores (PRS). Method We used a dataset from 23andMe (6.77M European, 1.30M Latine, and 0.45M African American individuals). Using cross-sectional data for PRS construction and a prospective cohort for evaluation, we estimated PRS-associated cumulative incidences after one year of follow-up for 12 clinical endpoints. Results The cumulative incidence of disease at one year was consistently higher among individuals in the top 10% of each PRS. Relative risks (RRs) comparing top to bottom 10% of PRS differed across diseases (e.g. European RR 2.12 for eczema vs 12.53 for T2D). Estimates were similar between Europeans and Latines however were more modest for African Americans (e.g. T2D RR 10.92 for Latines vs. 4.00 for African Americans). Clinical manifestation occurred earlier among those in top vs bottom 10% of polygenic risk: 16yrs for hypertension, and 9.5yrs for T2D. Among participants at elevated conventional risk of CHD or T2D, those in the top 10% PRS had a 10-20 fold higher RR of disease incidence vs those not at conventional risk. Among individuals at high polygenic risk of CHD or T2D, favorable lifestyle characteristics associated with 64-73% lower RR of developing disease over 1-year, with cumulative incidence equivalent to the population average. Conclusion In an ancestrally-diverse cohort, individuals in the top 10% PRS had higher 1-year disease incidence and earlier age of clinical manifestation. PRS provided risk stratification beyond conventional risk factors. Lifestyle characteristics markedly lowered disease incidence among those at elevated polygenic risk.

Abstract Hemophilia A is characterized by unpredictable spontaneous bleeds and chronic comorbidities. However, limited data exists at the national level into detailed management patterns related to patient clinical characteristics, representative real‐world dosing and treatment frequency, and costs. To assess and characterize the US severe hemophilia A (SHA) population, including subgroups of patients, in terms of clinical and demographic characteristics, healthcare resource utilization received at hemophilia treatment centers (HTCs), and projected annual costs of treatment utilizing data from the ATHNdataset of the American Thrombosis and Hemostasis Network (ATHN). Adult male people with SHA (PwSHA) (FVIII < 1%) were identified in the ATHNdataset between January 2013 and September 2019. This retrospective cohort study described patients’ demographic and clinical characteristics, clinical history, as well as the HTC‐related health resource utilization (HRU), treatment utilization, and projected annual treatment costs of US PwSHA received over the most recent year. Results are reported for the overall population and for three mutually exclusive subpopulations of patients: PwSHA with a history of and/or current inhibitors, PwSHA without a history of inhibitors but with (or a history of) one or more transfusion‐transmitted infections (hepatitis B virus [HBV], hepatitis C virus [HCV], or human immunodeficiency virus [HIV]), and PwSHA without a history of inhibitors or of transfusion‐transmitted infections (HBV, HCV, or HIV). Of the overall PwSHA cohort (N = 3677), there was a high prevalence of HCV (24.1%) and HIV (13.7%), while the prevalence of HBV (4.9%) was lower. Note that 20.5% of PwSHA overall currently or ever had FVIII inhibitors. On average, PwSHA had 2.8 total HTC visits per year, including 0.9 comprehensive care visits, 1.1 telephone contact visits, 0.5 office visits, and 0.1 surgeries or other procedures. However, 23.3% of PwSHA were not seen at an HTC, and 33.8% of PwSHA did not have a comprehensive care visit during their most recent year of data. HTC‐related HRU was similar between the overall cohort and across the patient subpopulations, although PwSHA and inhibitors had more frequent HTC visits (a mean of 3.6 visits annually vs. 2.5–2.8 in the other groups). Using reported treatment frequency and dosing, estimated mean annual hemophilia treatment costs varied by treatment and across the three subpopulations: extended half‐life factor product ($893,609–934,301 by subpopulation), standard half‐life factor product ($798,700–930,812), plasma‐derived factor product ($613,220–801,061), and non‐factor product treatment ($765,289—833,240). This study summarized recent sociodemographic and clinical characteristics, HTC‐related HRU, and HA treatments and projected costs among adult PwSHA, including among key subpopulations of PwSHA. PwSHA experience substantial clinical and resource burden on a chronic basis, despite the care coordination efforts of ATHN‐affiliated HTCs. These findings motivate further exploration of the drivers of resource utilization, observed differences across subpopulations and other disparities, and ongoing monitoring of clinical and treatment burden in the face of an evolving care landscape.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

Aims To assess real-world use of emicizumab in adult people with hemophilia A (PwHA) without inhibitors including healthcare resource utilization (HCRU) and costs. Materials and methods Adult, male PwHA without inhibitors initiating emicizumab (index date) were identified using IBM MarketScan after 4 October 2016. Patients were required to have continuous health insurance coverage for >= 180 days prior to and >= 90 days after index date and have >= 90 days of continuous use of emicizumab. Patients were followed until treatment gap, disenrollment, or end of data. Results were reported overall and among a subgroup with prior factor VIII (FVIII) prophylaxis. Emicizumab use, concomitant FVIII treatment use, HCRU, and costs were assessed separately over baseline, the emicizumab induction period, emicizumab maintenance period, and annualized. Results Among the 71 emicizumab patients (FVIII prophylaxis subgroup: 52) included in the study, the mean age was 35 (subgroup: 34) years and mean follow-up was 12 (subgroup: 11.1) months. At baseline, the annualized mean total healthcare cost was $532,948 (subgroup: $645,727). After emicizumab initiation, per-patient-per-month (PPPM) HCRU was higher in the emicizumab induction period compared to the maintenance period with higher monthly FVIII fills/in-office administrations (0.37 vs 0.17), non-FVIII outpatient visits (2.23 vs 1.55), and emergency department visits (0.06 vs 0.03). The FVIII prophylaxis subgroup yielded similar HCRU trends. Hemophilia treatment costs accounted for over 95% of total healthcare costs. The annualized mean cost was $50,491 (subgroup: $61,512) for concomitant FVIII treatment and $777,171 (subgroup: $793,168) for emicizumab and concomitant FVIII treatment for the first year of emicizumab treatment. Conclusion This study represented experience with emicizumab after the approval for PwHA without inhibitors. The study cohort may not be representative of all PwHA taking emicizumab. The findings highlight the continued burden of treatment and healthcare cost for PwHA without inhibitors despite advances in treatment options.

Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches. Genome-wide association meta-analysis of insomnia in 593,724 cases and 1,771,286 controls identifies 554 risk loci and implicates specific biological pathways through gene prioritization.

Objective Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Moving in synchrony to the beat is a fundamental component of musicality. Here, we conducted a genome-wide association study (GWAS) to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with sixty-nine loci reaching genome-wide significance (p<5×10 −8 ) and SNP-based heritability (on the liability scale) of 13%-16%. Heritability was enriched for genes expressed in brain tissues, and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central nervous system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through internet-based experiments) and of the GWAS (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed, and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.