Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.Peer reviewe

Advance Care Planning: A Comparison of Values Statements and Treatment Preferences

BACKGROUND: Advance directives (AD) with specific treatment preferences can be difficult to apply in actual clinical situations. As an alternative, advance directives that outline patient goals and values have been advocated. OBJECTIVE: To compare patient reactions to values-based and treatment-based advance directive forms. SETTING: Two academic general medicine outpatient clinics in Pittsburgh, Pa. METHODS: Outpatients age 55 or older who did not have an AD and were not demented were randomly assigned to complete either Emanuel's Medical Directive (EMD) or Pearlman's values history (PVH) form. MEASUREMENTS: Length of time to complete and number of questions asked about the AD forms; proportions of patients discussing the AD with family, designating a surrogate, returning the AD by mail, and desiring to have the AD in the medical record; patient ratings of AD by telephone interview; physician report of patient-initiated AD discussions. RESULTS: Of the 275 patients approached, 143 refused, 69 already had an AD, 63 patients were enrolled, and 25 in each group completed the telephone interview. A majority of individuals in both groups had conversations with others about the AD (60% EMD, 56% PVH; P = .77). All PVH forms designated a surrogate, whereas 79% of EMD forms did so (P = .02). One patient in each group initiated a conversation with his or her physician about AD following study completion. Both forms were thought to be a good first step in planning care at the end of life (92% EMD vs 84% PVH totally or mostly agree; P = .06). Patients completing the EMD thought it would give them control over the way their doctor cared for them at the end of their lives more than did the PVH group (84% EMD vs 48% PVH totally or mostly agree; P = .02). More patients completing the EMD form worried that it would be difficult to change answers on the form if they later changed their minds (20% EMD vs 4% PVH totally or mostly agree; P = .02). CONCLUSIONS: Both the values-based and treatment-based AD forms were rated favorably overall. Patients thought the treatment-based directive would give them more control over their care. Patients completing the values history form were more likely to designate a surrogate. Patients are likely to discuss both types of AD with family, but neither form alone is likely to lead to AD conversations with physicians