Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits.

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

HDAC1 overexpression enhances ß-cell proliferation by down-regulating Cdkn1b/p27.

The homeobox transcription factor Nkx6.1 is sufficient to increase functional ß-cell mass, where functional ß-cell mass refers to the combination of ß-cell proliferation, glucose-stimulated insulin secretion (GSIS) and ß-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional ß-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase ß-cell proliferation in primary rat islets and the INS-1 832/13 ß-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing ß-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated ß-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional ß-cell mass.

Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region.

The human leukocyte antigen (HLA) region plays an important role in human health through involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome-wide for 412,181 Finnish individuals and 2,459 traits. Across the 1,035 diseases with a GWAS association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 traits, including 1,750 associations uncovered by haplotype analysis. We find some haplotypes show trade-offs between diseases, while others consistently increase risk across traits, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk, and underscores the importance of classical and non-classical genes, as well as non-coding variation.

Factors of transurethral incision effectiveness for ureteroceles in pediatric patients: A 28-year, single-institution retrospective review.

BACKGROUND: As a congenital anomaly, ureteroceles occur in 1 in 4000 children, and are usually diagnosed prenatally. However, there remains a lack of definite consensus on the optimal management of congenital ureteroceles. OBJECTIVE: We evaluated factors associated with success of primary transurethral incision (TUI) in ureterocele pediatric patients. METHODS: Demographic and clinical information for 120 pediatric patients who were diagnosed with congenital ureterocele between 1993 and 2021 at our institution were obtained through retrospective chart review. Data were analyzed using Fisher's exact tests, t-tests, and logistic regression with a significance threshold of p < 0.05. The primary outcome of ureterocele management was TUI effectiveness, defined by no need for further surgical intervention. RESULTS: Of the 120 patients (39 boys, 81 girls) with ureteroceles, 75 patients (22 boys, 53 girls) met our inclusion criteria of undergoing initial TUI ureterocele. Initial TUI was effective in 51/75 patients (68.0%). We analyzed possible correlative factors for TUI efficacy. Simplex system was a significant predictor of primary TUI efficacy (85% effective in simplex systems, 62% in duplex systems). Prior urinary tract infection, prenatal diagnosis, and electrocautery technique were all associated with an increased risk of needing additional surgeries after primary TUI. DISCUSSION: The most significant predictors of effective primary TUI were simplex system and the absence of preoperative vesicoureteral reflux. Prenatal diagnosis, preoperative febrile urinary tract infection, higher preoperative hydronephrosis grade, and the use of electrocautery were all associated with decreased primary TUI efficacy. Study limitations include that it was a retrospective chart review, and cohort size was limited by incomplete urology follow-up and operative records. CONCLUSIONS: Initial TUI was an effective procedure for the majority of our pediatric ureterocele patients, a higher success rate compared to other cohorts. Patients with a simplex system were more likely to have an effective first TUI than patients with duplex systems, as were patients without preoperative reflux. Although not statistically significant, our data suggest prior UTI, prenatal diagnosis, higher preoperative hydronephrosis grade, and the use of electrocautery may be associated with having additional surgeries.

Transcriptomics and chromatin accessibility in multiple African population samples.

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation.

Pleiotropy and genetic correlation are widespread features in genome-wide association studies (GWAS), but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.

Short-Term Dairy Product Elimination and Reintroduction Minimally Perturbs the Gut Microbiota in Self-Reported Lactose-Intolerant Adults.

An outstanding question regarding the human gut microbiota is whether and how microbiota-directed interventions influence host phenotypic traits. Here, we employed a dietary intervention to probe this question in the context of lactose intolerance. To assess the effects of dietary dairy product elimination and (re)introduction on the microbiota and host phenotype, we studied 12 self-reported mildly lactose-intolerant adults with triweekly collection of fecal samples over a 12-week study period: 2 weeks of baseline diet, 4 weeks of dairy product elimination, and 6 weeks of gradual whole cow milk (re)introduction. Of the 12 subjects, 6 reported either no dairy or only lactose-free dairy product consumption. A clinical assay for lactose intolerance, the hydrogen breath test, was performed before and after each of these three study phases, and 16S rRNA gene amplicon sequencing was performed on all fecal samples. We found that none of the subjects showed change in a clinically defined measure of lactose tolerance. Similarly, fecal microbiota structure resisted modification. Although the mean fraction of the genus Bifidobacterium, a group known to metabolize lactose, increased slightly with milk (re)introduction (from 0.0125 to 0.0206; Wilcoxon P = 0.068), the overall structure of each subject's gut microbiota remained highly individualized and largely stable in the face of diet manipulation. IMPORTANCE Lactose intolerance is a gastrointestinal disorder diagnosed with a lactose hydrogen breath test. Lifestyle changes such as diet interventions can impact the gut microbiome; however, the role of the microbiome in lactose intolerance is unclear. Our study assessed the effects of a 12-week dietary dairy product elimination and (re)introduction on the microbiome and clinical lactose intolerance status in 12 adult self-reported lactose-intolerant individuals. We found each subject's gut microbiome remained highly individualized and largely stable in the face of this diet manipulation. We also report that none of the subjects showed change in a clinically defined measure of lactose tolerance.