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Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease affecting premature infants. In addition to prematurity itself and oxygen treatment, genetic factors have been suggested to predispose to ROP. We aimed to identify potentially pathogenic genes and biological pathways associated with ROP by analyzing variants from whole exome sequencing (WES) data of premature infants. As part of a multicenter ROP cohort study, 100 non-Hispanic Caucasian preterm infants enriched in phenotypic extremes were subjected to WES. Gene-based testing was done on coding nonsynonymous variants. Genes showing enrichment of qualifying variants in severe ROP compared to mild or no ROP from gene-based tests with adjustment for gestational age and birth weight were selected for gene set enrichment analysis (GSEA). Mean BW of included infants with pre-plus, type-1 or type 2 ROP including aggressive posterior ROP (n = 58) and mild or no ROP (n = 42) were 744 g and 995 g, respectively. No single genes reached genome-wide significance that could account for a severe phenotype. GSEA identified two significantly associated pathways (smooth endoplasmic reticulum and vitamin C metabolism) after correction for multiple tests. WES of premature infants revealed potential pathways that may be important in the pathogenesis of ROP and in further genetic studies.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides.

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare “clumping-and-thresholding” (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals. Here, the authors assess performance and limitations to polygenic risk scores in different race/ethnic groups. They find that polygenic risk score performance improves with diverse training data, and a better understanding of varying genetic backgrounds, social and environmental factors, and gene-environment interactions, is needed to enhance PRS performance for all groups.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P  <  6 × 10 − 10 after conditioning on previously reported variants, with effect sizes ranging from −7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits. Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.

Caroline Fox and colleagues report results of a genome-wide association study to identify common variants associated with indices of renal function. They show that variants at UMOD , a gene previously implicated in rare monogenic forms of kidney disease, are associated with risk of chronic kidney disease in the general population. Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity 1 . We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m 2 ) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations ( P < 5 × 10 −8 ) with CKD at the UMOD locus, with eGFRcrea at UMOD , SHROOM3 and GATM-SPATA5L1 , and with eGFRcys at CST and STC1 . UMOD encodes the most common protein in human urine, Tamm-Horsfall protein 2 , and rare mutations in UMOD cause mendelian forms of kidney disease 3 . Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B , pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

AbstractObjectiveTo investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.DesignIndividual participant data meta-analysis.Data sourcesEligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.Review methodsData from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.ResultsOf 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed.ConclusionsThese data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( P  < 5 × 10 − 9 ), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine. Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

BACKGROUNDMost GWAS of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry-enriched protein quantitative loci (pQTL).METHODSWe conducted a discovery GWAS of approximately 3,000 plasma proteins measured by the antibody-based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS) and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs was further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome-wide association study (PheWAS) across 2 large multiethnic electronic health record (EHR) systems in All of Us and BioMe.RESULTSWe identified 1,002 pQTLs for 925 protein assays. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for cathepsin L (CTSL) and Siglec-9, which were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, WBC count, and multiple sclerosis.CONCLUSIONSOur findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.FUNDINGNIH K08 HL161445-01A1; 5T32HL160522-03; HHSN268201600034I; HL133870.

Background Development of the placenta during the late first trimester is critical to ensure normal growth and development of the fetus. Developmental differences in this window such as sex-specific variation are implicated in later placental disease states, yet gene expression at this time is poorly understood. Methods RNA-sequencing was performed to characterize the transcriptome of 39 first trimester human placentas using chorionic villi following genetic testing (17 females, 22 males). Gene enrichment analysis was performed to find enriched canonical pathways and gene ontologies in the first trimester. DESeq2 was used to find sexually dimorphic gene expression. Patient demographics were analyzed for sex differences in fetal weight at time of chorionic villus sampling and birth. Results RNA-sequencing analyses detected 14,250 expressed genes, with chromosome 19 contributing the greatest proportion (973/2852, 34.1% of chromosome 19 genes) and Y chromosome contributing the least (16/568, 2.8%). Several placenta-enriched genes as well as histone-coding genes were identified to be unique to the first trimester and common to both sexes. Further, we identified 58 genes with significantly different expression between males and females: 25 X-linked, 15 Y-linked, and 18 autosomal genes. Genes that escape X inactivation were highly represented (59.1%) among X-linked genes upregulated in females. Many genes differentially expressed by sex consisted of X/Y gene pairs, suggesting that dosage compensation plays a role in sex differences. These X/Y pairs had roles in parallel, ancient canonical pathways important for eukaryotic cell growth and survival: chromatin modification, transcription, splicing, and translation. Conclusions This study is the first characterization of the late first trimester placenta transcriptome, highlighting similarities and differences among the sexes in ongoing human pregnancies resulting in live births. Sexual dimorphism may contribute to pregnancy outcomes, including fetal growth and birth weight, which was seen in our cohort, with males significantly heavier than females at birth. This transcriptome provides a basis for development of early diagnostic tests of placental function that can indicate overall pregnancy heath, fetal-maternal health, and long-term adult health.