Biology subjects

Hujoel, M. L. A.

Publications and source records attributed to Hujoel, M. L. A..

8 recordsLinked to original sources

bioRxiv2024

Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants

Expansions and contractions of tandem DNA repeats are a source of genetic variation in human populations and in human tissues: some expanded repeats cause inherited disorders, and some are also somatically unstable. We analyzed DNA sequence data, derived from the blood cells of >700,000 participants in UK Biobank and the All of Us Research Program, and developed new computational approaches to recognize, measure and learn from DNA-repeat instability at 15 highly polymorphic CAG-repeat loci. We found that expansion and contraction rates varied widely across these 15 loci, even for alleles of the same length; repeats at different loci also exhibited widely variable relative propensities to mutate in the germline versus the blood. The high somatic instability of TCF4 repeats enabled a genome-wide association analysis that identified seven loci at which inherited variants modulate TCF4 repeat instability in blood cells. Three of the implicated loci contained genes (MSH3, FAN1, and PMS2) that also modulate Huntingtons disease age-at-onset as well as somatic instability of the HTT repeat in blood; however, the specific genetic variants and their effects (instability-increasing or-decreasing) appeared to be tissue-specific and repeat-specific, suggesting that somatic mutation in different tissues--or of different repeats in the same tissue--proceeds independently and under the control of substantially different genetic variation. Additional modifier loci included DNA damage response genes ATAD5 and GADD45A. Analyzing DNA repeat expansions together with clinical data showed that inherited repeats in the 5 UTR of the glutaminase (GLS) gene are associated with stage 5 chronic kidney disease (OR=14.0 [5.7-34.3]) and liver diseases (OR=3.0 [1.5-5.9]). These and other results point to the dynamics of DNA repeats in human populations and across the human lifespan.

genetics↗

bioRxiv2023

Discovering chromatin dysregulation induced by protein-coding perturbations at scale

Although population-scale databases have expanded to millions of protein-coding variants, insight into variant mechanisms has not kept pace. We present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin. A pooled library of variants is expressed in a disease-agnostic cell line, and single-cell ATAC resolves each variants effect on chromatin. Using PROD-ATAC, we characterized the effects of >100 oncofusions (a class of cancer-causing chimeric proteins) and controls and revealed that pioneer activity is a common feature of fusions spanning an enormous range of fusion frequencies. Further, fusion-induced dysregulation can be context-agnostic as observed mechanisms often overlapped with cancer and cell-type specific prior knowledge. We also showed that gain-of-function pioneering is common among oncofusions. This work provides a global view of fusion-induced chromatin. We uncovered convergent mechanisms among disparate oncofusions and shared modes of dysregulation across different cancers. PROD-ATAC is generalizable to any set of protein-coding variants.

genomics↗

bioRxiv2023

Hidden protein-altering variants influence diverse human phenotypes

Structural variants (SVs) comprise the largest genetic variants, altering from 50 base pairs to megabases of DNA. However, SVs have not been effectively ascertained in most genetic association studies, leaving a key gap in our understanding of human complex trait genetics. We ascertained protein-altering SVs from UK Biobank whole-exome sequencing data (n=468,570) using haplotype-informed methods capable of detecting sub-exonic SVs and variation within segmental duplications. Incorporating SVs into analyses of rare variants predicted to cause gene loss-of-function (pLoF) identified 100 associations of pLoF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 appeared to confer one of the strongest protective effects of gene LoF on hypertension risk (OR = 0.86 [0.82-0.90]). Protein-coding variation in rapidly-evolving gene families within segmental duplications--previously invisible to most analysis methods--appeared to generate some of the human genomes largest contributions to variation in type 2 diabetes risk, chronotype, and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.

genetics↗

bioRxiv2021

Influences of rare copy number variation on human complex traits

The human genome contains hundreds of thousands of regions exhibiting copy number variation (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs (spanning tens of kilobases) have been ascertainable from the SNP-array data generated by large biobanks. We developed a new computational approach that leverages abundant haplotype-sharing in biobank cohorts to more sensitively detect CNVs co-inherited within extended SNP haplotypes. Applied to UK Biobank, this approach achieved 6-fold increased CNV detection sensitivity compared to previous analyses, accounting for approximately half of all rare gene inactivation events produced by genomic structural variation. This extensive CNV call set enabled the most comprehensive analysis to date of associations between CNVs and 56 quantitative traits, identifying 269 independent associations (P < 5 x 10-8) - involving 97 loci - that rigorous statistical fine-mapping analyses indicated were likely to be causally driven by CNVs. Putative target genes were identifiable for nearly half of the loci, enabling new insights into dosage-sensitivity of these genes and implicating several novel gene-trait relationships. CNVs at several loci created extended allelic series including deletions or duplications of distal enhancers that associated with much stronger phenotypic effects than SNPs within these regulatory elements. These results demonstrate the ability of haplotype-informed analysis to empower structural variant detection and provide insights into the genetic basis of human complex traits.

genetics↗

bioRxiv2021

Incorporating family history of disease improves polygenic risk scores in diverse populations

Polygenic risk scores derived from genotype data (PRS) and family history of disease (FH) both provide valuable information for predicting disease risk, enhancing prospects for clinical utility. PRS perform poorly when applied to diverse populations, but FH does not suffer this limitation. Here, we explore methods for combining both types of information (PRS-FH). We analyzed 10 complex diseases from the UK Biobank for which family history (parental and sibling history) was available for most target samples. PRS were trained using all British individuals (N=409K), and target samples consisted of unrelated non-British Europeans (N=42K), South Asians (N=7K), or Africans (N=7K). We evaluated PRS, FH, and PRS-FH using liability-scale R2, focusing on three well-powered diseases (type 2 diabetes, hypertension, depression) with R2 > 0.05 for PRS and/or FH in each target population. Averaging across these three diseases, PRS attained average prediction R2 of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average prediction R2 of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans; for each disease and each target population, the improvement was highly statistically significant. PRS-FH methods based on a logistic model and a liability threshold model performed similarly when covariates were not included in predictions (consistent with simulations), but the logistic model outperformed the liability threshold model when covariates were included. In conclusion, including family history greatly improves the accuracy of polygenic risk scores, particularly in diverse populations.

genetics↗

bioRxiv2019

Combining case-control status and family history of disease increases association power

Family history of disease can provide valuable information about an individuals genetic liability for disease in case-control association studies, but it is currently unclear how to best combine case-control status and family history of disease. We developed a new association method based on posterior mean genetic liabilities under a liability threshold model, conditional on both case-control status and family history (LT-FH); association statistics are computed via linear regression of genotypes and posterior mean genetic liabilities, equivalent to a score test. We applied LT-FH to 12 diseases from the UK Biobank (average N=350K). We compared LT-FH to genome-wide association without using family history (GWAS) and a previous proxy-based method for incorporating family history (GWAX). LT-FH was +63% (s.e. 6%) more powerful than GWAS and +36% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX, based on the number of independent genome-wide significant loci detected across all diseases (e.g. 690 independent loci for LT-FH vs. 423 for GWAS); the second best method was GWAX for lower-prevalence diseases and GWAS for higher-prevalence diseases, consistent with simulations. We also confirmed that LT-FH was well-calibrated (assessed via stratified LD score regression attenuation ratio), consistent with simulations. When using BOLT-LMM (instead of linear regression) to compute association statistics for all three methods (increasing the power of each method), LT-FH was +67% (s.e. 6%) more powerful than GWAS and +39% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX. In summary, LT-FH greatly increases association power in case-control association studies when family history of disease is available.

genetics↗

bioRxiv2018

Functional disease architectures reveal unique biological role of transposable elements

Transposable elements (TE) comprise roughly half of the human genome. Though initially derided as \"junk DNA\", they have been widely hypothesized to contribute to the evolution of gene regulation. However, the contribution of TE to the genetic architecture of diseases and complex traits remains unknown. Here, we analyze data from 41 independent diseases and complex traits (average N=320K) to draw three main conclusions. First, TE are uniquely informative for disease heritability. Despite overall depletion for heritability (54% of SNPs, 39{+/-}2% of heritability; enrichment of 0.72{+/-}0.03; 0.38-1.23 enrichment across four main TE classes), TE explain substantially more heritability than expected based on their depletion for known functional annotations (expected enrichment of 0.35{+/-}0.03; 2.11x ratio of true vs. expected enrichment). This implies that TE acquire function in ways that differ from known functional annotations. Second, older TE contribute more to disease heritability, consistent with acquiring biological function; SNPs inside the oldest 20% of TE explain 2.45x more heritability than SNPs inside the youngest 20% of TE. Third, Short Interspersed Nuclear Elements (SINE; one of the four main TE classes) are far more enriched for blood traits (2.05{+/-}0.30) than for other traits (0.96{+/-}0.09); this difference is far greater than expected based on the weaker depletion of SINEs for regulatory annotations in blood compared to other tissues. Our results elucidate the biological roles that TE play in the genetic architecture of diseases and complex traits.

genetics↗

bioRxiv2018

Disease heritability enrichment of regulatory elements is concentrated in elements with ancient sequence age and conserved function across species

Regulatory elements, e.g. enhancers and promoters, have been widely reported to be enriched for disease and complex trait heritability. We investigated how this enrichment varies with the age of the underlying genome sequence, the conservation of regulatory function across species, and the target gene of the regulatory element. We estimated heritability enrichment by applying stratified LD score regression to summary statistics from 41 independent diseases and complex traits (average N =320K) and meta-analyzing results across traits. Enrichment of human enhancers and promoters was larger in elements with older sequence age, assessed via alignment with other species irrespective of conserved functionality: enhancer elements with ancient sequence age (older than the split between marsupial and placental mammals) were 8.8x enriched (vs. 2.5x for all enhancers; p = 3e-14), and promoter elements with ancient sequence age were 13.5x enriched (vs. 5.1x for all promoters; p = 5e-16). Enrichment of human enhancers and promoters was also larger in elements whose regulatory function was conserved across species, e.g. human enhancers that were enhancers in [≥]5 of 9 other mammals were 4.6x enriched (p = 5e-12 vs. all enhancers). Enrichment of human promoters was larger in promoters of loss-of-function intolerant genes: 12.0x enrichment (p = 8e-15 vs. all promoters). The mean value of several measures of negative selection within these genomic annotations mirrored all of these findings. Notably, the annotations with these excess heritability enrichments were jointly significant conditional on each other and on our baseline-LD model, which includes a broad set of coding, conserved, regulatory and LD-related annotations.

genetics↗