No abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10−245). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.

BackgroundDespite its health benefits, physical inactivity is pervasive, particularly among those living in lower-income urban communities. In such settings, neighborhood safety may impact willingness to be regularly physically active. We examined the association of perceived neighborhood safety with pedometer-determined physical activity and physical activity self-efficacy.Methods and FindingsParticipants were 1,180 predominantly racial/ethnic minority adults recruited from 12 urban low-income housing complexes in metropolitan Boston. Participants completed a 5-d pedometer data-collection protocol and self-reported their perceptions of neighborhood safety and self-efficacy (i.e., confidence in the ability to be physically active). Gender-stratified bivariate and multivariable random effects models were estimated to account for within-site clustering. Most participants reported feeling safe during the day, while just over one-third (36%) felt safe at night. We found no association between daytime safety reports and physical activity among both men and women. There was also no association between night-time safety reports and physical activity among men (p = 0.23) but women who reported feeling unsafe (versus safe) at night showed significantly fewer steps per day (4,302 versus 5,178, p = 0.01). Perceiving one's neighborhood as unsafe during the day was associated with significantly lower odds of having high physical activity self-efficacy among both men (OR 0.40, p = 0.01) and women (OR 0.68, p = 0.02).ConclusionsResiding in a neighborhood that is perceived to be unsafe at night is a barrier to regular physical activity among individuals, especially women, living in urban low-income housing. Feeling unsafe may also diminish confidence in the ability to be more physically active. Both of these factors may limit the effectiveness of physical activity promotion strategies delivered in similar settings.