Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

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Previous studies indicate that subjectively reported and objectively measured sleep abnormalities at baseline can increase the risk of relapse in treated alcoholics. However, previous studies did not include both subjective and objective sleep measures in the same group of patients. We utilized polysomnography and the Sleep Disorders Questionnaire to determine if baseline polysomnography increased the ability to predict relapse beyond the prediction with subjective measures alone, after controlling for nonsleep variables that were associated with relapse. We followed 74 patients with a DSM-III-R diagnosis of alcohol dependence, of whom 36 relapsed to at least some drinking during an average follow-up interval of 5 months. Univariate analyses revealed that relapsed patients did not differ from abstinent patients at baseline in demographics or psychiatric co-morbidity, but they had more prior treatment episodes for alcoholism, more difficulty falling asleep, more complaints of abnormal sleep, and, on polysomnography, longer sleep latencies, shorter rapid eye movement sleep latencies, and less stage 4 sleep percentage than abstinent patients. With a series of logistic regression analyses, which controlled for age and gender, we demonstrated that sleep measures improved the prediction model compared with nonsleep variables alone, and that polysomnography-measured sleep latency was the most significant predictor variable. We conclude that subjective and objective measures of baseline sleep are predictors of relapse in treated alcoholic patients. These data also suggest that neurophysiological dysfunction contributes strongly to the etiology of relapse. Finally, sleep disturbance warrants clinical attention as a target of alcoholism treatment.

Previous studies indicate that subjectively reported and objectively measured sleep abnormalities at baseline can increase the risk of relapse in treated alcoholics. However, previous studies did not include both subjective and objective sleep measures in the same group of patients. We utilized polysomnography and the Sleep Disorders Questionnaire to determine if baseline polysomnography increased the ability to predict relapse beyond the prediction with subjective measures alone, after controlling for nonsleep variables that were associated with relapse. We followed 74 patients with a DSM-III-R diagnosis of alcohol dependence, of whom 36 relapsed to at least some drinking during an average follow-up interval of 5 months. Univariate analyses revealed that relapsed patients did not differ from abstinent patients at baseline in demographics or psychiatric co-morbidity, but they had more prior treatment episodes for alcoholism, more difficulty falling asleep, more complaints of abnormal sleep, and, on polysomnography, longer sleep latencies, shorter rapid eye movement sleep latencies, and less stage 4 sleep percentage than abstinent patients. With a series of logistic regression analyses, which controlled for age and gender, we demonstrated that sleep measures improved the prediction model compared with nonsleep variables alone, and that polysomnography-measured sleep latency was the most significant predictor variable. We conclude that subjective and objective measures of baseline sleep are predictors of relapse in treated alcoholic patients. These data also suggest that neurophysiological dysfunction contributes strongly to the etiology of relapse. Finally, sleep disturbance warrants clinical attention as a target of alcoholism treatment.

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Objective-Sleep problems are common, costly, and potentially fatal in older adults. Sleep problems are also commonly associated with alcoholism. Yet, few studies have examined the combined effects of alcoholism and aging on sleep. The purpose of this study was to investigate the main and interactive effects of diagnostic group and age group on sleep.Method-Male and female alcohol-dependent patients (N=139) and non-alcoholic controls (N=87) completed full-montage polysomnography, structured psychiatric diagnostic interviews, validated rating scales, and alcohol histories at the University of Michigan between 1989 and 1996. The sample was divided for analytic purposes into older (55+ yr) and younger (<55 yr) subgroups.Results-After controlling for gender, race, body mass index, and psychiatric-related sleep symptoms, alcoholics and older adults had significantly decreased total sleep time and increased stage 1 sleep percentage, respiratory distress, and periodic limb movements. Older adults also had decreased delta sleep percentage and shorter rapid eye movement (REM) sleep latencies. Significant interactions were found between alcoholism and age group for stage 1 sleep percentage, sleepdisordered breathing, and periodic limb movements with older alcoholics having the most disturbances. Older alcoholics also had the highest mean values for sleep latency and the lowest mean values for sleep efficiency and delta sleep percentage when compared to the other three groups.Conclusions-Older alcoholics have increased sleep disturbances when compared to younger alcoholics and non-alcoholics of both age groups. Care providers should screen for sleep problems among older adults with alcohol problems.

Sleep apnea and related disorders contribute to disturbed sleep in abstinent alcoholics. In an earlier report from our group, sleep-disordered breathing was common and increased with age in a cohort of 75 abstinent alcoholics. We now report an extension of the previous work that includes studies of an additional 103 abstinent alcoholics undergoing treatment for alcoholism (total sample = 188) and a comparison group of 87 normal subjects. The presence and severity of sleep-disordered breathing was assessed with polysomnography. Among the alcoholics, sleep-disordered breathing (defined as 10 or more apneas plus hypopneas per hour of sleep) was present in 3% of 91 subjects under age 40, 17% of 83 subjects age 40 to 59, and 50% of 14 subjects age 60 or over. Subjects with sleep-disordered breathing were more likely to be male and had more severe sleep disruption and nocturnal hypoxemia and more complaints related to daytime sleepiness than subjects without sleep-disordered breathing. In a multiple linear regression analysis, age and body mass index were significant predictors of the presence of sleep-disordered breathing, whereas smoking history and duration of heavy drinking were not predictors after controlling for the effects of age and body mass index. Our findings suggest that sleep-disordered breathing contributes significantly to sleep disturbance in a substantial proportion of older alcoholics and that symptomatic sleep-disordered breathing increases with age in alcoholics. Sleep-disordered breathing, when combined with existing cardiovascular risk factors, may contribute to adverse health consequences in alcoholics.