INTRODUCTION Studies have suggested sleep duration may be associated with Alzheimer’s disease risk, but findings based on self-reported sleep duration are likely to be influenced by reverse causation and residual confounding bias. METHODS A polygenic score (PGS) for device-measured sleep duration was constructed using LDpred2-auto in 77,770 white British UK Biobank participants. We applied the PGS to 264,746 white British participants independent of the sample from which the PGS was developed. We assessed the association of fifths of genetically predicted sleep duration with Alzheimer’s disease risk (1,451 cases/264,746 individuals over median 12.5y of follow-up). RESULTS The PGS explained ∼2% of variation in device-measured sleep duration. Compared to individuals in the middle fifth of PGS, those in the highest fifth (indicating ∼15 mins/day longer sleep) had a lower risk of Alzheimer’s disease (HR=0.79[95%CI,0.67-0.94]). DISCUSSION Our results indicate that genetic predisposition to relatively long sleep duration is associated with a lower Alzheimer’s disease risk. ### Competing Interest Statement MVH is a full-time employee of 23andMe, Inc and holds stock in the company. MVH has an honorary academic position at the University of Bristol. MVH has previously consulted for Boehringer Ingelheim, and in adherence to the staff policy of his previous employer (the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit), did not accept personal honoraria or other payments from pharmaceutical companies. ATYW, AD, KSB, RCT, GKR, SF, and CVD have declared no competing interests. ### Funding Statement The UK Biobank application associated with the current study is 59070. ATYW is supported by a Nuffield Department of Population Health (NDPH) Early Career Research Fellowship. AD is supported by the Wellcome Trust [223100/Z/21/Z], Novo Nordisk, Swiss Re, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the British Heart Foundation Centre of Research Excellence (grant number RE/18/3/34214), the Alan Turing Institute and the British Heart Foundation (grant number SP/18/4/33803), and Health Data Research UK, an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. KSB is funded by The Cancer Research UK Programme grant (C8221/A29017). SF and GKR are PIs of the Million Women Study which is funded by Cancer Research UK (A29186). MVH was supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512). RCT is funded by Cancer Research UK (C8221/A29017). Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ### 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: Ethics approval for UK Biobank was obtained from the National Health Service North West Centre for Research Ethics Committee (11/NW/0382). Informed consent was collected from all UK Biobank participants. (for more information please visit ) 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Please refer to for details of UK Biobank.

BACKGROUNDKidney stone disease (KSD) affects approximately 10% of adults, is heritable, and is associated with mineral metabolic abnormalities.METHODSGenetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using GWAS, region-specific Mendelian randomization (MR), and genetic colocalization. The utility of pathway modulation was estimated via drug target MR, and the effects of variants on calcium-sensing receptor (CaSR) signaling were characterized.RESULTSSeventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified 3 loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (ORs for genomic regions = 4.30, 11.42, and 13.83 per 1 SD alteration; P < 5.6 × 10-10). Colocalization analyses defined putative, noncoding KSD-causing variants estimated to account for 11%-19% of KSD cases in proximity to diacylglycerol kinase δ (DGKD), a CaSR signaling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug target MR indicated that reducing serum calcium by 0.08 mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16 mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR allosteric modulator.CONCLUSIONDGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalized KSD risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.FUNDINGOxfordshire Health Services Research Committee (OHSRC, part of Oxford Hospitals Charity); Kidney Research UK (RP_030_20180306); The Urology Foundation; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (NF-SI-0514-10091); Wellcome Trust (204826/z/16/z and 106995/z/15/z); Medical Research Council (MRC) Clinical Research Training Fellowships (MR/W03168X/1 and MR/S021329/1); Wellcome Trust Clinical Career Development Fellowship; Sir Henry Dale Fellowship, with joint funding by the Wellcome Trust and the Royal Society (224155/Z/21/Z); St. Peter's Trust for Kidney Bladder and Prostate Research.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1-3. Despite gene editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer cells and dendritic cells increased between postoperative day (POD) 10 and 28, concordant with an expansion of IgG and IgA B cell clonotypes and subsequent biopsy-confirmed antibody-mediated rejection (AMR) at POD33. Human T cell frequencies increased from POD14 and peaked between POD33 and POD49 in the blood and xenograft, which coincided with T cell receptor diversification, expansion of a restricted TRBV2 and TRBJ1 clonotype and histological evidence of combined AMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, which aligned with interferon-γ-driven inflammation and a T helper 1-type immune response. There was also evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury marked by S100A6 (ref. 5), SPP1 (also known as osteopontin)6 and COLEC11 (ref. 7) expression at POD21-POD33. Proteomic profiling revealed activation of human and pig complement, with a decreased human component after AMR therapy, in which complement was inhibited. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney and reveal potential immunomodulatory targets for improving xenograft survival.

Depression is a frequent focus of interest in genetic testing. Despite the growing availability of polygenic risk scores (PRSs) for depression, little is known about the psychological impact of receiving them in real-world settings. To quantify the impact of receiving an at-risk depression PRS result on depression and anxiety symptoms, we conducted a longitudinal, prospective cohort study of 23andMe research participants. Eligible participants were US residents 18 years old and older who completed two surveys between October 19, 2022 and October 9, 2023 assessing depression and anxiety symptoms and who had an at-risk PRS for depression (odds ratio ≥1.5). We compared 361 individuals who viewed their result with 556 who did not. Primary outcomes were changes in depression (Patient Health Questionnaire-8) and anxiety (Depression Anxiety Stress Scale-21) symptom scores relative to baseline. We fitted linear regressions to model each outcome, adjusting for age, sex, ancestry, income, prior depression and/or anxiety, and baseline scores. Using an equivalence testing framework, the smallest effect size of interest was defined as Cohen's d = ±0.5. Score changes from baseline to follow-up were statistically equivalent for individuals who viewed results and those who did not (adjusted between-group differences in score changes: depression, -0.17 points [90% confidence interval {CI} -0.59 to 0.24]; anxiety, -0.092 points [90% CI -0.35 to 0.17]; all p < 0.001). Results were consistent in substrata with or without prior depression or anxiety. We conclude that among genetically at-risk individuals, exposure to a depression PRS result was well tolerated in a real-world setting.

Polygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer. We conducted a PRS survival analysis using 23,770 cancer patients of European ancestry from the Dana-Farber Cancer Institute Profile cohort. We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89 (95

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.

Adult height is a highly heritable polygenic trait with heritability attributable to thousands of independent variants. Large-scale studies have been able to detect genetic variants with contributions to height in the range of approximately 1.2 millimetre per allele copy on average. Non-additive genetic interactions may, in part, account for the difference between broad-sense and narrow-sense heritability estimates. However, prior studies have failed to identify variants with non-additive effects, possibly due to the lack of statistical power. Leveraging 3.6M individuals of European genetic ancestry in the 23andMe research cohort, we performed a genome-wide analysis study (GWAS) to select 1,063 independent common SNPs associated with height (p-value < 5e-8), and then screened for evidence of non-additive effects by analysing 564,453 models including a pairwise SNP-SNP interaction term. We identified 69 pairwise models with suggestive evidence of SNP-SNP interaction (p-value < 1e-4) and, for each SNP pair, we evaluated a fully saturated model including additive, dominant, and epistatic (additive-by-additive, additive-by-dominance and dominance-by-dominance) terms. We tested for the presence of epistatic interactions by comparing models with and without epistatic terms using a likelihood ratio test. Assuming a strict Bonferroni-corrected threshold of 8.9e-8 (0.05/564,453), we found no evidence of epistatic interactions (Likelihood ratio test (LRT) p-value < 9e-07 for all models). Our analysis rules out the existence of epistatic interactions between alleles of >1% frequency with effect sizes larger than 2.42mm. Our large-scale analysis provides further evidence of the minimal contribution of non-additivity in the genetic architecture of adult human height. ### Competing Interest Statement M.R.J., M.V.H., D.H., A.A and P.F. are employed by and hold stock or stock options in 23andMe, Inc.

A substantial proportion of acute SARSCoV2 infection cases exhibit gastrointestinal symptoms, yet the genetic determinants of these extrapulmonary manifestations are poorly understood. Using survey data from 239,866 individuals who tested positively for SARSCoV2, we conducted a multi-ancestry GWAS of 80,289 cases of diarrhea occurring during acute COVID19 infection (33.5%). Six loci (CYP7A1, LZFTl1/CCR9, TEME182, NALCN, LFNG, GCKR) met genomewide significance in a trans-ancestral analysis. The top significant GWAS hit mapped to the CYP7A1 locus, which plays an etiologic role in bile acid metabolism and is in high LD (r2= 0.93) with the SDCBP gene, which was previously implicated in antigen processing and presentation in the COVID-19 context. Another association was observed with variants in the LZTFL1/CCR9 region, which is a known locus for COVID19 susceptibility and severity. PheWAS showed a shared association across three of the six SNPs with irritable bowel syndrome (IBS) and its subtypes. Mendelian randomization showed that genetic liability to IBS-diarrhea increased (OR=1.40,95%,CI[1.33,1.47]), and liability to IBS-constipation decreased (OR=0.86, 95%CI[0.79,0.94]) the relative odds of experiencing COVID19+ diarrhea. Our genetic findings provide etiological insights into the extrapulmonary manifestations of acute SARSCoV2 infection.### Competing Interest StatementC.H.W, P.N, S,A, and M.V.H are current employees of 23andMe and hold stock or stock options in 23andMe. J.S is a current employee of Bristol Myers Squibb. N.S.C works as a postdoctoral fellow on the 23andMe Genetic Epidemiology Team. ### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The surveys were distributed to individuals who provided informed consent and volunteered to participate in the research online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent (E&I) Review Services. As of 2022, E&I Review Services is part of Salus IRBI 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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe full set of GWAS summary statistics can be made available to qualified investigators upon request and signing agreement with 23andMe to protect participant confidentiality. The information can be accessed at https://research.23andme.com/covid19-dataset-access/

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.

MAP3K15 has been previously associated with protection from type 2 diabetes (T2D), prompting interest in the development of MAP3K15 inhibitors as a potential therapeutic option for diabetes. The trans-ancestry genome-wide association study (GWAS) meta-analysis and loss-of-function (LoF) burden testing methods that implicate association with T2D greatly benefit from large sample size. The direct-to-consumer genetic testing company, 23andMe, Inc., is the world's largest research consented genetic database. We leveraged the 23andMe database to further inform the metabolic role of MAP3K15, using a variety of genetic analysis methods. We find that MAP3K15 LoF carriers show a significant delay of 4.5 years in the median age of T2D diagnosis among individuals at high polygenic risk and uncover a novel burden association of MAP3K15 LoF with protection against high cholesterol. We expanded these findings by establishing a capability to recruit consented participants on the basis of genetics unknown to them, (specifically, a single LoF variant in MAP3K15, rs148312150) and obtained clinical laboratory evidence of a modest reduction in median cholesterol and LDL/HDL ratio in MAP3K15 LoF carriers. Our findings demonstrate the discovery power of the 23andMe database, including the feasibility of consented participant recruitment to inform therapeutic discovery and development.### Competing Interest StatementAll authors are current or former employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. J.J.B. is an option holder at Variant Bio.### Funding StatementThis study did not receive any funding.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Participants provided informed consent and volunteered to participate in the research online under a protocol approved by the external AAHRPP-accredited Salus IRB (https://www.versiticlinicaltrials.org/salusirb). All research was performed in accordance with relevant guidelines/regulations, including the Declaration of Helsinki. 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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesGiven restrictions to the availability of 23andMe individual-level data owing to 23andMe consent and privacy/IRB guidelines, data sharing is limited to aggregate statistics that are necessary for reproducibility. Broader data sharing pertaining to the data/samples supporting the findings of this study may be made available upon reasonable request or collaboration, to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants, in accordance with individual consent and additional requirements within the scope of our IRB approval.

Aims Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition.Methods and results In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 x 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 x 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI.Conclusion The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.Lay summary Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease. PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD). These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

The etiology of Long COVID is poorly understood despite its estimated global burden of 65 million cases. There exists a paucity of genetic studies that can shed light on potential mechanisms leading to Long COVID. Using consented and genotyped data from 23andMe adult research participants, we conducted the largest multi-ancestry meta-analysis of genome-wide association studies of Long COVID across European (42,899 cases, 94,721 controls), Latinx (8,631 cases, 20,351 controls), and African-American (2,234 cases, 5,596 controls) genetic ancestry groups. GWAS of Long COVID identified three genome-wide significant loci (HLA-DQA1 and HLA-DQB, ABO, BPTF:KPAN2:C17orf58). Functional analysis of these genes points to underlying immune and thrombo-inflammatory mechanisms. We present evidence of shared genetic architecture (genetic correlation p-value < 0.001) of Long COVID with thirteen phenotypes of similar symptomatology or pathophysiology. We identified potential causal roles from liability to chronic fatigue (Mendelian randomization OR=1.59, 95% CI[1.51,1.66]), fibromyalgia (OR=1.54, 95% CI[1.49,1.60]), and depression (OR=1.53, 95% CI[1.46,1.61]) with Long COVID, which replicated in the COVID-19 Host Genetics Initiative data, and which are unlikely to originate from collider bias. These findings can help identify populations vulnerable to Long COVID and inform future therapeutic approaches. ### Competing Interest Statement C.H.W, P.N, S,A, and M.V.H are current employees of 23andMe and hold stock or stock options in 23andMe. N.S.C works as a postdoctoral fellow on the 23andMe Genetic Epidemiology Team. ### Funding Statement This study was funded by 23andMe Inc. ### 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: Individuals participating in this study provided informed consent and conducted survey participation online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent Review Services (E&I Review, now Salus IRB). 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 The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Datasets will be made available at no cost for academic use. Please visit https://research.23andme.com/collaborate/#dataset-access/ for more information and to apply to access the data

Early detection of Parkinson’s disease (PD), a neurodegenerative disease with central and peripheral nerve involvement, ensures timely treatment access. Microbes influence nervous system health and are altered in PD. We examined gut and mouth microbiomes from recently diagnosed patients in a geographically diverse, matched case-control, metagenomics study. We demonstrated greater alpha-diversity in 464 PD patients versus 249 controls. The microbial signature of PD included overabundance of 16 OTUs, including Streptococcus mutans and Bifidobacterium dentium , and depletion of 28 OTUs. Machine learning models indicated sub-species level oral microbiome abundances best distinguished PD with relatively high accuracy (area under the curve: 0.758). Microbial networks were disrupted in cases, with reduced connectivity of short-chain fatty acid-producing bacteria from stool. Microbiome diversity metrics associated with non-motor autonomic symptom severity. Our results provide evidence for predictive oral taxonomic PD microbiome signatures that may be useful for early detection, particularly with peripheral nervous system involvement.

Mendelian randomization (MR) is a genetic epidemiological technique that uses genetic variation to infer causal relationships between modifiable exposures and outcome variables. Conventional observational epidemiological studies are subject to bias from a range of sources; MR analyses can offer an advantage in that they are less prone to bias as they use genetic variants inherited at conception as "instrumental variables", which are proxies of an exposure. However, as with all research tools, MR studies must be carefully designed to yield valuable insights into causal relationships between exposures and outcomes, and to avoid biased or misleading results that undermine the validity of the causal inferences drawn from the study. In this review, we outline Mendel's laws of inheritance, the assumptions and principles that underlie MR, MR study designs and methods, and how MR analyses can be applied and reported. Using the example of serum phosphate concentrations on liability to kidney stone disease we illustrate how MR estimates may be visualized and, finally, we contextualize MR in bone and mineral research including exemplifying how this technique could be employed to inform clinical studies and future guidelines concerning BMD and fracture risk. This review provides a framework to enhance understanding of how MR may be used to triangulate evidence and progress research in bone and mineral metabolism as we strive to infer causal effects in health and disease.

Miscarriage is a common adverse pregnancy outcome, impacting approximately 15% of pregnancies. Herein, we present results of the largest trans-ancestral genome wide association study for miscarriage to date, based on 334,593 cases of sporadic, and 52,087 cases of recurrent miscarriage in the 23andMe, Inc. Research Cohort. We identified 10 novel genome-wide significant associations for sporadic miscarriage, and one for recurrent miscarriage. These loci mapped to genes with roles in neural development and telomere length, and to developmental disorders including autism spectrum disorder. Three variants, with similar directionality and magnitude of effect, replicated in a previously published GWAS. Using Mendelian randomization and triangulation, robust evidence was found for smoking causally increasing the risk of sporadic (genetic liability to ever vs never smoking: OR 1.13; 95%CI: 1.11-1.15; P=2.61e-42) and recurrent (OR 1.25; 95%CI: 1.21-1.30; P=5.47e-34) miscarriage, with moderate, yet triangulating, evidence identified for a potential etiological role of caffeine consumption. ### Competing Interest Statement Authors are employed by and hold stock with 23andMe, Inc. ### Funding Statement This study was funded by 23andMe, Inc. ### 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: Individuals participating in this study provided informed consent and conducted survey participation online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent Review Services (E&I Review, now Salus IRB). 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 The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Datasets will be made available at no cost for academic use. Please visit for more information and to apply to access the data.

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.

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.

BackgroundEarly detection of Parkinson's disease (PD), a neurodegenerative disease with central and peripheral nerve involvement, ensures timely treatment access. Microbes influence nervous system health and are altered in PD.MethodsWe examined gut and mouth microbiomes from recently diagnosed patients in a geographically diverse, matched case-control, shotgun metagenomics study.ResultsHere, we show greater alpha-diversity in 445 PD patients versus 221 controls. The microbial signature of PD includes overabundance of 16 OTUs, including Streptococcus mutans and Bifidobacterium dentium, and depletion of 28 OTUs. Machine learning models indicate that subspecies level oral microbiome abundances best distinguish PD with reasonably high accuracy (area under the curve: 0.758). Microbial networks are disrupted in cases, with reduced connectivity between short-chain fatty acid-producing bacteria the the gut. Importantly, microbiome diversity metrics are associated with non-motor autonomic symptom severity.ConclusionsOur results provide evidence that predictive oral PD microbiome signatures could possibly be used as biomarkers for the early detection of PD, particularly when there is peripheral nervous system involvement. Stagaman et al. investigate the associations between early idiopathic Parkinson's disease (PD) and the diversity and composition of both saliva and stool microbiomes in a large, geographically diverse US cohort. Abundances of saliva microbes, particularly Prevotella, Neisseria, and Streptococcus OTUs, best distinguish between controls and cases. Parkinson's disease (PD) is a neurodegenerative disease that is characterized by both motor symptoms, such as tremors, and non-motor symptoms, such as constipation. Our aim was to determine whether there were differences in the number and types of microbes living in the saliva and intestines of people with and without PD. We saw significant differences in the microbial communities living in healthy controls compared to people with PD. Additionally, we found that the proportions of microbe types in saliva were the best at distinguishing between controls and cases, and identified the specific kinds of microbes that were driving this distinction. These results highlight the potential importance of the saliva microbiome in understanding the causes and symptomatology of PD.