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Background Diarrhea is the second leading cause of death in children under 5 years old worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics in diarrhea. Methods Using 3 well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies. Results For diarrhea frequency, we identified 2 genome-wide significant loci associated with not having any diarrhea, on chromosome 21 within the noncoding RNA AP000959 (C allele odds ratio [OR] = 0.31, P = 4.01 × 10−8), and on chromosome 8 within SAMD12 (T allele OR = 0.35, P = 4.74 × 10−7). For duration of diarrhea, we identified 2 loci associated with no diarrhea, including the same locus on chromosome 21 (C allele OR = 0.31, P = 1.59 × 10−8) and another locus on chromosome 17 near WSCD1 (C allele OR = 0.35, P = 1.09 × 10−7). Conclusions These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.

Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. These strategies have benefited from improvements in imputation methods and association tests, however little attention has been paid to ways in which array design can increase rare variant association power. Therefore, we developed a novel framework to select tag SNPs using the reference panel of 26 populations from Phase 3 of the 1000 Genomes Project. We evaluate tag SNP performance via mean imputed r2 at untyped sites using leave-one-out internal validation and standard imputation methods, rather than pairwise linkage disequilibrium. Moving beyond pairwise metrics allows us to account for haplotype diversity across the genome for improve imputation accuracy and demonstrates population-specific biases from pairwise estimates. We also examine array design strategies that contrast multi-ethnic cohorts vs. single populations, and show a boost in performance for the former can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Using our framework, we demonstrate increased imputation accuracy for rare variants (frequency < 1%) by 0.5–3.1% for an array of one million sites and 0.7–7.1% for an array of 500,000 sites, depending on the population. Finally, we show how recent explosive growth in non-African populations means tag SNPs capture on average 30% fewer other variants than in African populations. The unified framework presented here will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.

To confirm previously identified polymorphisms in HAVCR1 that were associated with persistent hepatitis C virus (HCV) infection in individuals of African and of European descent, we studied 165 subjects of African descent and 635 subjects of European descent. Because the association was only confirmed in subjects of African descent (rs6880859; odds ratio, 2.42; P = .01), we then used 379 subjects of African descent (142 with spontaneous HCV clearance) to fine-map HAVCR1. rs111511318 was strongly associated with HCV persistence after adjusting for IL28B and HLA (adjusted P = 8.8 × 10(-4)), as was one 81-kb haplotype (adjusted P = .0006). The HAVCR1 genomic region is an independent genetic determinant of HCV persistence in individuals of African descent.