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Original Investigation |

Alcohol Use Disorder and Mortality Across the Lifespan A Longitudinal Cohort and Co-relative Analysis

Kenneth S. Kendler, MD1,2,3; Henrik Ohlsson, PhD4; Jan Sundquist, MD, PhD4; Kristina Sundquist, MD, PhD4
[+] Author Affiliations
1Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond
2Department of Psychiatry, Virginia Commonwealth University, Richmond
3Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond
4Center for Primary Health Care Research, Lund University, Malmö, Sweden
JAMA Psychiatry. 2016;73(6):575-581. doi:10.1001/jamapsychiatry.2016.0360.
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Importance  Excess alcohol consumption and alcohol use disorders (AUDs) are associated with substantially increased mortality. Efforts to reduce this toll require an understanding of their causes.

Objective  To clarify the degree to which the excess mortality associated with AUDs arises (1) from the predispositions of the person who develops AUD (and which would likely be shared by close relatives) and (2) as a direct result of AUD itself.

Design, Setting, and Participants  A prospective cohort and co-relative design study involving all individuals born in Sweden from 1940 to 1965 who had neither died nor migrated prior to 1973 or age 15 years (N = 2 821 036). They were followed up from January 1, 1973, until December 31, 2010. Alcohol use disorder was assessed from medical, criminal, and pharmacy registries. Half-siblings, full-siblings, and monozygotic twin pairs discordant for AUD were obtained from the Multi-Generation and Twin Register.

Main Outcome and Measure  Death obtained from the Swedish Death registry.

Results  Our cohort (1 447 887 males and 1 373 149 females) included 131 895 males and 42 163 females registered with AUD. The mean (SD) age at first AUD registration was 39 (13.4) years. We ascertained 127 347 and 76 325 deaths in the male and female subsamples, respectively. Controlling for sex, educational status, and year of birth, the mortality hazard ratio associated with AUD was 5.83 (95% CI, 5.76-5.90) and varied—with an inverted U-shaped function—by age. Examining the AUD-mortality association in the general population and in relative pairs discordant for AUD exposure demonstrated substantial familial confounding in early to mid-adulthood: the AUD-associated mortality hazard ratio was much lower in discordant close relatives than in the general population. In middle to late adulthood, evidence for familial confounding decreased with increasing evidence for a direct effect of AUD on elevated mortality. In the oldest age group (65-70 years), the mortality hazard ratios were similar across the population and all relative pairs, suggesting that the excess mortality was largely a result of having AUD. Adding years since onset of AUD to the model showed that both increasing age and increasing years of duration of AUD contributed to the reduction of familial confounding in the association between AUD and elevated mortality.

Conclusions and Relevance  Excess mortality associated with AUD arises both from the predispositions of the person who develops AUD and the direct result of having AUD. The effect of predisposition is more prominent early in the life course and in the early years of AUD. The direct effect of AUD becomes progressively more important later in life and with longer duration of AUD. These results have implications for interventions seeking to reduce the elevated AUD-associated mortality.

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Figure 1.
Observed Hazard Ratio in the General Population for Death as the Outcome With Alcohol Use Disorder Registration as a Time-Dependent Coefficient as a Function of Age

Sex, educational status, and year of birth are included in the model as covariates.

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Figure 2.
Expected Hazard Ratio for Death as the Outcome With Alcohol Use Disorder Registration as a Time-Dependent Coefficient as a Function of Age in 9 Age Groups From Late Adolescence to Late Adulthood

Sex, educational status, and year of birth are included in the model as covariates. Estimated hazard ratios are presented for the general population and in half-siblings, full-siblings, and monozygotic twins discordant for alcohol use disorder.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Hazard Ratio for Death as the Outcome With Alcohol Use Disorder (AUD) Registration as a Time-Dependent Coefficient as a Function of Age From Late Adolescence to Late Adulthood and Within Each Age Group as a Function of Years Since First AUD Registration

Sex, educational status, and year of birth are included in the model as covariates. Estimated hazard ratios are presented for the general population and in half-siblings, full-siblings, and monozygotic twins discordant for AUD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Evidence for Familial Confounding of the Alcohol Use Disorder (AUD)–Mortality Association as a Function Both of Age and Time Since First AUD Registration

The figure depicts the hazard ratio for the genetic slope in the general population and pairs of discordant half-siblings, full-siblings, and monozygotic twins. The lower the value for the slope, the more evidence there is for familial confounding. A slope of unity indicates no confounding consistent with the hypothesis that all the effect of AUD on mortality is causal.

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