Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

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.

The UGT2A1/UGT2A2 locus is associated with COVID-19-related loss of smell or taste.

Using online surveys, we collected data regarding COVID-19-related loss of smell or taste from 69,841 individuals. We performed a multi-ancestry genome-wide association study and identified a genome-wide significant locus in the vicinity of the UGT2A1 and UGT2A2 genes. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants. These findings provide a genetic link to the biological mechanisms underlying COVID-19-related loss of smell or taste.

Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Underrecognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. RESEARCH QUESTION: The study addressed three questions: (1) Does a DTC testing service identify previously undetected individuals with AATD? (2) What was the interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and (3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? STUDY DESIGN AND METHODS: In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. RESULTS: Among 195,014 study participants, the allele frequency for the PI∗S and PI∗Z AATD variants was 21.6% (6.5% for PI∗Z and 15.1% for PI∗S); 0.63% were PI∗ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with health care providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI∗ZZ individuals shared their DTC result with an HCP. The OR for PI∗ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 (95% CI = 1.4-2.2) compared with those without a Z allele and for reduced alcohol consumption this was 4.0 (95% CI = 2.6-5.9). INTERPRETATION: In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19 susceptibility and severity.

COVID-19 presents with a wide range of severity, from asymptomatic in some individuals to fatal in others. Based on a study of 1,051,032 23andMe research participants, we report genetic and nongenetic associations with testing positive for SARS-CoV-2, respiratory symptoms and hospitalization. Using trans-ancestry genome-wide association studies, we identified a strong association between blood type and COVID-19 diagnosis, as well as a gene-rich locus on chromosome 3p21.31 that is more strongly associated with outcome severity. Hospitalization risk factors include advancing age, male sex, obesity, lower socioeconomic status, non-European ancestry and preexisting cardiometabolic conditions. While non-European ancestry was a significant risk factor for hospitalization after adjusting for sociodemographics and preexisting health conditions, we did not find evidence that these two primary genetic associations explain risk differences between populations for severe COVID-19 outcomes.

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.

Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.

BACKGROUND: Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals. OBJECTIVE: We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD). METHODS: Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800µg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. RESULTS: High FA intake (≥800µg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800µg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models. CONCLUSIONS: In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.

Longitudinal analysis of changes in weight and waist circumference in relation to incident vasomotor symptoms: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: Greater body mass index (BMI) and body fat are associated with vasomotor symptoms (VMS). Thus, weight loss may prevent VMS. We analyzed whether concurrent BMI or waist circumference and/or changes in weight or waist circumference predicted incident VMS and whether these relations differed by menopause stage or race/ethnicity. METHODS: Data from 10 follow-up visits for 1,546 participants in the Study of Women's Health Across the Nation who reported no VMS at baseline were modeled for time to first symptomatic visit in relation to concurrent BMI and waist circumference and change in weight and waist circumference during early and late menopause using discrete survival analyses, adjusting for covariates. RESULTS: Greater concurrent BMI and waist circumference were significantly related to greater any and frequent (≥6 d in the last 2 wk) incident VMS in early menopause and lower VMS risk in late menopause. Percentage weight change since baseline and since the prior visit was unrelated to incident any VMS in either menopause stage. Percentage weight change since baseline had a significant shallow U-shaped association with incident frequent VMS in early menopause (P = 0.02), a shallow inverse U-shape in late menopause (P = 0.02), and a significant interaction with menopause stage (P = 0.004) but not with race/ethnicity. Recent weight change was unassociated with incident VMS in either menopause stage. Results were similar for waist change. CONCLUSIONS: Concurrent BMI and waist circumference were positively related to incident VMS in early menopause and negatively related in late menopause. Maintaining healthy weight in early menopause may help prevent VMS.

Life without plastic: A family experiment and biomonitoring study.

Exposure to bisphenol-A (BPA) and phthalates has been associated with negative health outcomes in animal and human studies, and human bio-monitoring studies demonstrate widespread exposure in the US and Europe. Out of concern for the environment and health, individuals may attempt to modify their environment, diet, and consumer choices to avoid such exposures, but these natural experiments are rarely if ever quantitatively evaluated. The aim of the study was to evaluate the difference in urinary concentrations of BPA and phthalate metabolites following an exposure reduction intervention among an Austrian family of five. Urine samples were taken shortly after the family had removed all plastic kitchenware, toys, and bathroom products, and started a concerted effort to eat less food packaged in plastic. Two-months later, urine samples were collected at a follow-up visit, and concentrations of BPA and phthalate metabolites were compared. Shortly after removal of plastic urinary concentrations of BPA were below limit of quantification in all samples. Phthalate concentrations were low, however, 10 of 14 investigated metabolites could be found above limit of quantification. After the two-month intervention, phthalate urinary concentrations had declined in some but not all family members. In the mother most phthalate metabolites increased. The low levels might be partly due to the environmentally conscious lifestyle of the family and partly due to the fact that body levels had dropped already because of the delay of four days between finishing removal and first measurement. Further two months avoidance of dietary exposure and exposure to environmental plastics reduced urinary concentrations for all but one metabolite in the oldest son only, but decreased somewhat in all family members except the mother.

Indoor Environmental Quality in Mechanically Ventilated, Energy-Efficient Buildings vs. Conventional Buildings.

Energy-efficient buildings need mechanical ventilation. However, there are concerns that inadequate mechanical ventilation may lead to impaired indoor air quality. Using a semi-experimental field study, we investigated if exposure of occupants of two types of buildings (mechanical vs. natural ventilation) differs with regard to indoor air pollutants and climate factors. We investigated living and bedrooms in 123 buildings (62 highly energy-efficient and 61 conventional buildings) built in the years 2010 to 2012 in Austria (mainly Vienna and Lower Austria). Measurements of indoor parameters (climate, chemical pollutants and biological contaminants) were conducted twice. In total, more than 3000 measurements were performed. Almost all indoor air quality and room climate parameters showed significantly better results in mechanically ventilated homes compared to those relying on ventilation from open windows and/or doors. This study does not support the hypothesis that occupants in mechanically ventilated low energy houses are exposed to lower indoor air quality.

Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study.

BACKGROUND: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism. OBJECTIVES: We evaluated whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) study. METHODS: The CHARGE study is a population-based case-control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316). RESULTS: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified. CONCLUSIONS: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.

Tipping the balance of autism risk: potential mechanisms linking pesticides and autism.

BACKGROUND: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features. OBJECTIVES: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk. METHODS: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism. DISCUSSION: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition. CONCLUSIONS: In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.

Independent and dependent contributions of advanced maternal and paternal ages to autism risk.

Reports on autism and parental age have yielded conflicting results on whether mothers, fathers, or both, contribute to increased risk. We analyzed restricted strata of parental age in a 10-year California birth cohort to determine the independent or dependent effect from each parent. Autism cases from California Department of Developmental Services records were linked to State birth files (1990-1999). Only singleton births with complete data on parental age and education were included (n=4,947,935, cases=12,159). In multivariate logistic regression models, advancing maternal age increased risk for autism monotonically regardless of the paternal age. Compared with mothers 25-29 years of age, the adjusted odds ratio (aOR) for mothers 40+ years was 1.51 (95% CI: 1.35-1.70), or compared with mothers <25 years of age, aOR=1.77 (95% CI, 1.56-2.00). In contrast, autism risk was associated with advancing paternal age primarily among mothers <30: aOR=1.59 (95% CI, 1.37-1.85) comparing fathers 40+ vs. 25-29 years of age. However, among mothers >30, the aOR was 1.13 (95% CI, 1.01-1.27) for fathers 40+ vs. 25-29 years of age, almost identical to the aOR for fathers <25 years. Based on the first examination of heterogeneity in parental age effects, it appears that women's risk for delivering a child who develops autism increases throughout their reproductive years whereas father's age confers increased risk for autism when mothers are <30, but has little effect when mothers are past age 30. We also calculated that the recent trend towards delayed childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.

Caspase cleavage of the nonstructural protein NS1 mediates replication of Aleutian mink disease parvovirus.

Virus-induced apoptosis of infected cells can limit both the time and the cellular machinery available for virus replication. Hence, many viruses have evolved strategies to specifically inhibit apoptosis. However, Aleutian mink disease parvovirus (ADV) is the first example of a DNA virus that not only induces apoptosis but also utilizes caspase activity to facilitate virus replication. To determine the function of caspase activity during ADV replication, virus-infected cell lysates or purified ADV proteins were incubated with various purified caspases. Caspases cleaved the major nonstructural protein of ADV (NS1) at two caspase recognition sequences, whereas ADV structural proteins could not be cleaved. Importantly, the NS1 products could be identified in ADV-infected cells but were not present in infected cells pretreated with caspase inhibitors. By mutating putative caspase cleavage sites (D to E), we mapped the two cleavage sites to amino acid residues NS1:227 (INTD downward arrow S) and NS1:285 (DQTD downward arrow S). Replication of ADV containing either of these mutations was reduced 10(3)- to 10(4)-fold compared to that of wild-type virus, and a construct containing both mutations was replication defective. Immunofluorescent studies revealed that cleavage was required for nuclear localization of NS1. The requirement for caspase activity during permissive replication suggests that limitation of caspase activation and apoptosis in vivo may be a novel approach to restricting virus replication.