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Asthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and -adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene, SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of the NFKB1 variants demonstrated by our functional assays. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years to interrogate a broad range of traits, across diverse populations. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power for trait mapping, and will enable studies of genome biology, population genetics and genome function at unprecedented scale. A central challenge for joint analysis is that different WGS data processing and analysis pipelines cause substantial batch effects in combined datasets, necessitating computationally expensive reprocessing and harmonization prior to variant calling. This approach is no longer tenable given the scale of current studies and data volumes. Here, in a collaboration across multiple genome centers and NIH programs, we define WGS data processing standards that allow different groups to produce \"functionally equivalent\" (FE) results suitable for joint variant calling with minimal batch effects. Our approach promotes broad harmonization of upstream data processing steps, while allowing for diverse variant callers. Importantly, it allows each group to continue innovating on data processing pipelines, as long as results remain compatible. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results including single nucleotide (SNV), insertion/deletion (indel) and structural variation (SV) and produce significantly less variability than sequencing replicates. Residual inter-pipeline variability is concentrated at low quality sites and repetitive genomic regions prone to stochastic effects. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for broad data sharing and community-wide \"big-data\" human genetics studies.

Increased LDL-cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease (CVD). We identified novel associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.5 mg/dl lower LDL-C (p=1.6E-15), and 26 mg/dl lower plasma fibrinogen (p= 9.8E-05). N-linked glycan profiling found p.Asn352Ser to be associated (p-values from 1.4E-06 to 1.0E-17) with decreased glycosylation of glycoproteins including: fibrinogen, ApoB100, immunoglobulin G (IgG), and transferrin. In vitro assays found that the mutant (352Ser) protein had 50% lower galactosyltransferase activity compared to wild type (352Asn) protein. Knockdown of b4galt1 in zebrafish embryos resulted in significantly lower LDL-C compared to control, which was fully rescued by co-expression of 352Asn human B4GALT1 mRNA but only partially rescued by co-expression of 352Ser human B4GALT1 mRNA. Our findings establish B4GALT1 as a novel gene associated with lower LDL-C and fibrinogen and suggest that targeted modulation of protein glycosylation may represent a therapeutic approach to decrease CVD risk.