Summary/AbstractGenome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development, and clinical guidelines. However, the dominance of European-ancestry populations in GWAS creates a biased view of the role of human variation in disease, and hinders the equitable translation of genetic associations into clinical and public health applications. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioral phenotypes in 49,839 non-European individuals. Using strategies designed for analysis of multi-ethnic and admixed populations, we confirm 574 GWAS catalog variants across these traits, and find 38 secondary signals in known loci and 27 novel loci. Our data shows strong evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts, and insights into clinical implications. We strongly advocate for continued, large genome-wide efforts in diverse populations to reduce health disparities.

1The emergence of very large cohorts in genomic research has facilitated a focus on 2 genotype-imputation strategies to power rare variant association. Consequently, a new generation 3 of genotyping arrays are being developed designed with tag single nucleotide polymorphisms 4 (SNPs) to improve rare variant imputation. Selection of these tag SNPs poses several challenges 5 as rare variants tend to be continentally-or even population-specific and reflect fine-scale linkage 6 disequilibrium (LD) structure impacted by recent demographic events. To explore the landscape of 7 tag-able variation and guide design considerations for large-cohort and biobank arrays, we 8 developed a novel pipeline to select tag SNPs using the 26 population reference panel from Phase 9 3 of the 1000 Genomes Project. We evaluate our approach using leave-one-out internal validation 10 via standard imputation methods that allows the direct comparison of tag SNP performance by 11 estimating the correlation of the imputed and real genotypes for each iteration of potential array 12 sites. We show how this approach allows for an assessment of array design and performance that 13 can take advantage of the development of deeper and more diverse sequenced reference panels. 14 We quantify the impact of demography on tag SNP performance across populations and provide 15 population-specific guidelines for tag SNP selection. We also examine array design strategies that 16 target single populations versus multi-ethnic cohorts, and demonstrate a boost in performance for 17 the latter can be obtained by prioritizing tag SNPs that contribute information across multiple 18 populations simultaneously. Finally, we demonstrate the utility of improved array design to provide 19 meaningful improvements in power, particularly in trans-ethnic studies. The unified framework 20 presented will enable investigators to make informed decisions for the design of new arrays, and 21 help empower the next phase of rare variant association for global health. 22

Study question: What is the genetic basis of preeclampsia in Andean families residing at high altitudes? Summary answer: A top candidate region associated with preeclampsia containing clotting factor genes PROZ, F7 and F10 was found on chromosome 13 of the fetal genome in affected Andean families. What is known already: Preeclampsia, a multi-organ complication of pregnancy, is a leading cause of maternal morbidity and mortality worldwide. Diagnosed by the onset of maternal hypertension and proteinuria after 20 weeks of gestation, this disorder is a common cause of preterm delivery and affects approximately 5-7% of global pregnancies. The heterogeneity of preeclampsia has posed a challenge in understanding its etiology and molecular basis. However, risk for the condition is known to increase in high altitude regions such as the Peruvian Andes. Study design, size, duration: To investigate the genetic basis of preeclampsia in a high-altitude resident population, we characterized genetic diversity in a cohort of Andean families (N=883) from Puno, Peru, a high-altitude city above 3,500 meters. Our study collected DNA samples and medical records from case-control trios and duos between 2011-2016, thus allowing for measurement of maternal, paternal, and fetal genetic factors influencing preeclampsia risk. Participants/materials, setting, methods: We generated high-density genotype data for 439,314 positions across the genome, determined ancestry patterns and mapped associations between genetic variants and preeclampsia phenotype. We also conducted fine mapping of potential causal variants in a subset of family participants and tested ProZ protein levels in post- partum maternal and cord blood plasma by ELISA. Main results and the role of chance: A transmission disequilibrium test (TDT) revealed variants near genes of biological importance in pregnancy physiology for placental and blood vessel function. The most significant SNP in this cluster, rs5960 (p<6x10-6) is a synonymous variant in the clotting factor F10. Two other members of the coagulation cascade, F7 and PROZ, are also in the top associated region. However, we detected no difference of PROZ levels in maternal or umbilical cord plasma. Limitations, reasons for caution: Our genome-wide association analysis (GWAS) was limited by a small sample size and lack of functional follow up. Our ELISA was limited to post-natal blood sampling (only samples collected immediately after birth). But, despite a small sample size, our family based GWAS design permits identification of novel significant and suggestive associations with preeclampsia. Further longitudinal studies could analyze clotting factor levels and activity in other pregnant cohorts in Peru to assess the impact of thrombosis in preeclampsia risk among Andean highlanders. Wider implications of the findings: These findings support previous evidence suggesting that coagulation plays an important role in the pathology of preeclampsia and potentially underlies susceptibility to other pregnancy disorders exacerbated at high altitudes. This discovery of a novel association related to a functional pathway relevant to pregnancy biology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.