A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Substance-related diagnosis type predicts the likelihood and co-occurrence of preterm and cesarean delivery.

This article aimed to evaluate whether a substance-related diagnosis (SRD; i.e., alcohol, opioids, cannabis, stimulants, nicotine) predicts the likelihood and co-occurrence of preterm (20-37 weeks' gestation) and cesarean delivery.This study reviewed electronic health record data on women (aged 18-44 years) who delivered a single live or stillbirth at ≥ 20 weeks of gestation from 2012 to 2019. Women with and without an SRD were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios and 95% confidence intervals were calculated.Of the 19,346 deliveries, a matched cohort of 2,158 deliveries was identified. Of these, 1,079 (50%) had an SRD, 280 (13%) had a preterm delivery, 833 (39%) had a cesarean delivery, and 166 (8%) had a co-occurring preterm and cesarean delivery. An SRD was significantly associated with preterm and cesarean delivery (AOR = 1.84 [95% CI, 1.41-2.39], p-value= <0.0001; AOR = 1.51 [95% CI, 1.23-1.85], p-value= <0.0001). An alcohol-related diagnosis (AOR = 1.82 [95% CI, 1.01-3.28], p-value= 0.0471), opioid-related diagnosis (AOR = 1.94 [95% CI, 1.26-2.98], p-value= 0.0027), stimulant-related diagnosis (AOR = 1.65 [95% CI, 1.11-2.45], p-value= 0.0142), and nicotine-related diagnosis (AOR = 1.54 [95% CI, 1.05-2.26], p-value= 0.0278) were associated with co-occurring preterm and cesarean delivery.Pregnant women with an SRD experienced disproportionally higher odds of preterm and cesarean delivery compared to pregnant women without an SRD. Substance-type predicts the type of delivery outcome. An SRD in pregnant women should be identified early to reduce potential harm through intervention and treatment.

Differences in outpatient, emergency, and inpatient use among pregnant women with a substance-related diagnosis.

BACKGROUND: As a vulnerable population, pregnant women with a substance-related diagnosis (ie, substance use, misuse, or dependence) may use healthcare disproportionately. OBJECTIVE: The primary goal of this study was to evaluate the differences in the use of outpatient clinical visits, emergency department visits, and inpatient days in the hospital among women with and without a substance-related diagnosis during the antepartum period. STUDY DESIGN: This retrospective study retrieved electronic health record data on women (age, 18-44 years) who delivered a single live birth or stillbirth at ≥20 weeks of gestation from April 1, 2012, to September 30, 2019. Imbalance in measured maternal sociodemographic and obstetrical characteristics between women with and without a substance-related diagnosis was attenuated using propensity score matching on key demographic characteristics (eg, age), yielding a matched 1:1 sample. Unadjusted and adjusted logistic regressions models were used to determine the association between a substance-related diagnosis and outpatient visits, emergency visits, and inpatient days. RESULTS: From the total sample (n=16,770), the matched cohort consisted of 1986 deliveries. Of these, most were White (51.0%), or mixed or of some other race (31.1%). The mean age was 29.8 (standard deviation, 5.6). A substance-related diagnosis was identified in 993 women (50%) because of matching. Women with a substance-related diagnosis were more likely to have ≤10 outpatient visits than women without a substance-related diagnosis (adjusted odds ratio, 1.81 [95% confidence interval, 1.44-2.28]; P<.0001). Alcohol-, opioid-, and stimulant-related diagnoses were independently associated with ≤10 outpatient visits (adjusted odds ratio, 3.16 [95% confidence interval, 1.67-6.04]; P=.0005; adjusted odds ratio, 3.02 [95% confidence interval, 1.79-5.09]; P<.0001; adjusted odds ratio, 2.18 [95% confidence interval, 1.39-3.41]; P=.0007, respectively). Women with a substance-related diagnosis were more likely to have ≥1 emergency visit than women without a substance-related diagnosis (adjusted odds ratio, 1.36 [95% confidence interval, 1.00-1.85]; P<.0001). Opioid-, stimulant-, and nicotine-related diagnoses were independently associated with ≥1 emergency visit (adjusted odds ratio, 2.28 [95% confidence interval, 1.09-4.77]; P=.0287; adjusted odds ratio, 2.01 [95% confidence interval, 1.07-3.78]; P=.0301; adjusted odds ratio, 3.38 [95% confidence interval, 1.90-6.02]; P<.0001, respectively). Women with a substance-related diagnosis were more likely to have ≥3 inpatient days than women without a substance-related diagnosis (adjusted odds ratio, 1.69 [95% confidence interval, 1.07-2.67]; P=.0256). Opioid-, stimulant-, and nicotine-related diagnosis were independently associated with ≥3 inpatient days (adjusted odds ratio, 3.52 [95% confidence interval, 1.42-8.75]; P=.0067; adjusted odds ratio, 3.51 [95% confidence interval, 1.31-9.34]; P=.0123; adjusted odds ratio, 2.74 [95% confidence interval, 1.11-6.73]; P=.0285, respectively). CONCLUSION: Women with a substance-related diagnosis during the antepartum period who delivered a single live birth or stillbirth at ≥20 weeks of gestation were experiencing fewer outpatient visits, more emergency department visits, and more inpatient days than women without a substance-related diagnosis. The type of substance-related diagnosis (eg, alcohol, opioids, stimulants, or nicotine) was associated with different patterns of healthcare use. The results from this study have reinforced the need to identify substance-related diagnoses in pregnant women early to minimize disproportionate healthcare service utilization through intervention and treatment.