Biology subjects

Lin, H. J.

Publications and source records attributed to Lin, H. J..

5 recordsLinked to original sources

bioRxiv2022

The functional impact of rare variation across the regulatory cascade

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis (MESA) which included several hundred individuals with whole genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, ten years apart. We evaluated each multi-omic phenotypes ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62x and rare frameshift variants 216x as frequently as controls, compared to 13x to 27x for expression or protein effects alone. We developed a Bayesian hierarchical model to prioritize specific rare variants underlying multi-omic signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimers disease.

genomics↗

bioRxiv2019

Multi-ethnic genome-wide association study of decomposed cardioelectric phenotypes illustrates strategies to identify and characterize evidence of shared genetic effects for complex traits

BackgroundPublished genome-wide association studies (GWAS) are mainly European-centric, examine a narrow view of phenotypic variation, and infrequently interrogate genetic effects shared across traits. We therefore examined the extent to which a multi-ethnic, combined trait GWAS of phenotypes that map to well-defined biology can enable detection and characterization of complex trait loci.\n\nMethodsWith 1000 Genomes Phase 3 imputed data in 34,668 participants (15% African American; 3% Chinese American; 51% European American; 30% Hispanic/Latino), we performed covariate-adjusted univariate GWAS of six contiguous electrocardiogram (ECG) traits that decomposed an average heartbeat and two commonly reported composite ECG traits that summed contiguous traits. Combined phenotype testing was performed using the adaptive sum of powered scores test (aSPU).\n\nResultsWe identified six novel and 87 known ECG trait loci (aSPU p-value < 5E-9). Lead SNP rs3211938 at novel locus CD36 was common in African Americans (minor allele frequency=10%) and near-monomorphic in European Americans, with effect sizes for the composite trait, QT interval, among the largest reported. Only one novel locus was detected for the composite traits, due to opposite directions of effects across contiguous traits that summed to near-zero. Combined phenotype testing did not detect novel loci unapparent by univariate testing. However, this approach aided locus characterization, particularly when loci harbored multiple independent signals that differed by trait.\n\nConclusionsDespite including one-third as few participants as the largest published GWAS of ECG traits, our study identifies multiple novel ECG genetic loci, emphasizing the importance of ancestral diversity and phenotype measurement in this era of ever-growing GWAS.\n\nAUTHOR SUMMARYWe leveraged a multiethnic cohort with precise measures of cardioelectric function to identify novel genetic loci affecting this complex, multifaceted phenotype. The success of our approach stresses the importance of phenotypic precision and participant diversity for future locus discovery and characterization efforts, and cautions against compromises made in genome-wide association studies to pursue ever-growing sample sizes.

epidemiology↗

bioRxiv2019

An open resource of structural variation for medical and population genetics

Structural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large ([≥]1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.

genomics↗

bioRxiv2018

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.\n\nMethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.\n\nResultsWe identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top association in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56x10-26) in SCN5A/SCN10A. Three additional previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.\n\nConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

genetics↗

bioRxiv2018

Loss-of-function in IRF2BPL is associated with neurological phenotypes

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

genetics↗