The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

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Background Conventional multi-session genetic counseling is currently recommended when disclosing APOE genotype for risk of Alzheimer’s disease (AD) in cognitively normal individuals. Objective To evaluate the safety of brief disclosure protocols for disclosing APOE genotype for risk of Alzheimer’s disease (AD). Methods A randomized, multicenter non-inferiority trial was conducted at 4 sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared to condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Pre-planned co-primary outcomes were anxiety and depression scales 12 months after disclosure. Results 343 adults (mean age 58.3, range 33–86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n= 115), CP-GC protocol (n=116) or CP-MD protocol (n=112). Mean post-disclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC to SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all p<0.001 on non-inferiority tests), establishing non-inferiority for condensed protocols. Results were similar between European Americans and African Americans. Conclusions These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

Purpose Telephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes. Methods In a multisite trial of Alzheimer’s disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in-person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure. Results Data from 257 participants showed that telephone disclosure occurred 7.4 days sooner and were 30% shorter, on average, than in-person disclosure (both p<0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% CIs of mean differences were within non-inferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Sub-analyses supported non-inferiority on all outcomes among APOE ε4-negative participants. Sub-analyses were inconclusive for APOE ε4-positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern. Conclusion Telephone disclosure of APOE results and risk for Alzheimer’s disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease.