Richard Border
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View article: A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects
A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects Open
The contribution of genetic interactions (epistasis) to human complex trait variation remains poorly understood due, in part, to the statistical and computational challenges involved in testing for interaction effects. Here we introduce FA…
View article: Leveraging protein language models to identify complex trait associations with previously inaccessible classes of functional rare variants
Leveraging protein language models to identify complex trait associations with previously inaccessible classes of functional rare variants Open
Protein language models (PLMs) improve variant effect predictions, but their role in gene discovery for complex traits remains unclear. We introduce an allelic series-based regression test that uses PLM-derived variant effect predictions a…
View article: Comprehensive gene heritability estimation reveals the genetic architecture of rare coding variants underlying complex traits
Comprehensive gene heritability estimation reveals the genetic architecture of rare coding variants underlying complex traits Open
Whole-exome sequencing (WES) enables high-resolution interrogation of the contribution of rare coding variants to complex trait variation. However, existing methods for heritability estimation attributed to rare-coding variants are often l…
View article: The geometry of <i>G</i> × <i>E</i>: how scaling and endogenous treatment effects shape interaction direction
The geometry of <i>G</i> × <i>E</i>: how scaling and endogenous treatment effects shape interaction direction Open
Gene-environment interaction ( G × E ) studies hold promise for identifying genetic loci mediating the effects of environmental risk on disease. However, interpretation of G × E effects is often confounded by two fundamental issues: the de…
View article: Identifying novel genetic and phenotypic associations to genomic features by leveraging off-target reads in exome sequencing data
Identifying novel genetic and phenotypic associations to genomic features by leveraging off-target reads in exome sequencing data Open
Upwards of 40% of reads in sequencing datasets may be unmapped and discarded by standard protocols. Recent work has shown the utility of re-analyzing these unmapped reads to construct meaningful features, such as immune diversity repertoir…
View article: Simple models of non-random mating and environmental transmission bias standard human genetics statistical methods
Simple models of non-random mating and environmental transmission bias standard human genetics statistical methods Open
There is recognition among human complex-trait geneticists that not only are many common assumptions made for the sake of statistical tractability (e.g., random mating, independence of parent/offspring environments) unlikely to apply in ma…
View article: Family-GWAS reveals effects of environment and mating on genetic associations
Family-GWAS reveals effects of environment and mating on genetic associations Open
Genome–wide association studies (GWAS) have discovered thousands of replicable genetic associations, guiding drug target discovery and powering genetic prediction of human phenotypes and diseases. However, genetic associations can be affec…
View article: Assortative mating across nine psychiatric disorders is consistent and persistent over cultures and generations
Assortative mating across nine psychiatric disorders is consistent and persistent over cultures and generations Open
Emerging evidence has shown that assortative mating (AM) is a key factor that shapes the landscape of complex human traits. It can increase the overall prevalence of disorders, influence occurrences of comorbidities, and bias estimation of…
View article: No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples
No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples Open
Objective: Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this contro…
View article: Meta-analysis of Genome wide Association Studies on Childhood ADHD Symptoms and Diagnosis Reveals 17 Novel Loci and 22 Potential Effector Genes
Meta-analysis of Genome wide Association Studies on Childhood ADHD Symptoms and Diagnosis Reveals 17 Novel Loci and 22 Potential Effector Genes Open
Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder for which genetic factors explain up to 75% of the variance. In this study, we performed a genome-wide association meta-analysis (GWAMA) of ADHD sym…
View article: Characterizing the genetic architecture of drug response using gene-context interaction methods
Characterizing the genetic architecture of drug response using gene-context interaction methods Open
Identifying the factors responsible for variability of treatment response is a central objective of clinical research. Specially designed pharmacogenomic studies have identified a handful of individual mutations modulating the effect of sp…
View article: Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions
Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions Open
Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mec…
View article: rBahadur: efficient simulation of structured high-dimensional genotype data with applications to assortative mating
rBahadur: efficient simulation of structured high-dimensional genotype data with applications to assortative mating Open
Existing methods for generating synthetic genotype data are ill-suited for replicating the effects of assortative mating (AM). We propose _, a novel and computationally efficient algorithm for generating high-dimensional binary random vari…
View article: Cross-trait assortative mating is widespread and inflates genetic correlation estimates
Cross-trait assortative mating is widespread and inflates genetic correlation estimates Open
The observation of genetic correlations between disparate human traits has been interpreted as evidence of widespread pleiotropy. Here, we introduce cross-trait assortative mating (xAM) as an alternative explanation. We observe that xAM af…
View article: rBahadur: Efficient simulation of high-dimensional genotype data with global dependence structures
rBahadur: Efficient simulation of high-dimensional genotype data with global dependence structures Open
Summary Existing methods for generating synthetic genotype data are ill-suited for replicating the effects of assortative mating (AM). We propose rb_dplr , a novel and computationally efficient algorithm for generating high-dimensional bin…
View article: Loci on Chromosome 20 Interact with rs16969968 to Influence Cigarettes per Day in European Ancestry Individuals
Loci on Chromosome 20 Interact with rs16969968 to Influence Cigarettes per Day in European Ancestry Individuals Open
Our understanding of the molecular genetic contributions to smoking are limited to the additive effects of individual single nucleotide polymorphisms (SNPs), but the underlying genetic risk is likely to also include dominance, epistatic, a…
View article: Phenotype integration improves power and preserves specificity in biobank-based genetic studies of MDD
Phenotype integration improves power and preserves specificity in biobank-based genetic studies of MDD Open
Biobanks often contain several phenotypes relevant to a given disorder, and researchers face complex tradeoffs between shallow phenotypes (high sample size, low specificity and sensitivity) and deep phenotypes (low sample size, high specif…
View article: Cross-trait assortative mating is widespread and inflates genetic correlation estimates
Cross-trait assortative mating is widespread and inflates genetic correlation estimates Open
The observation of genetic correlations between disparate traits has been interpreted as evidence of widespread pleiotropy, altered theories of human genetic architecture, and spurred considerable research activity across the natural and s…
View article: Genetic association study of childhood aggression across raters, instruments, and age.
Genetic association study of childhood aggression across raters, instruments, and age. Open
Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assesso…