Modified penetrance of coding variants by cis-regulatory variation contributes to the trait of disease risk

This topic is important to these GEITP pages, but it is not trivial to understand. Variable penetrance is defined as the extent to which a particular gene(s) is(are) expressed in the phenotype (trait) of individuals carrying it –– as measured by that percentage of carriers in a population that exhibit the trait. Variable expressivity denotes the range of phenotypic variance of an expressed trait that can occur in different individuals having the same genotype.

Variable penetrance and variable expressivity are common phenomena that can be seen in interindividual responses to a drug or to an environmental toxicant. Therefore, this topic is highly relevant to these GEITP pages. Authors [see attached report] use the term ‘variable penetrance’ as a joint description of both variable expressivity (severity of phenotype) and penetrance (proportion of carriers showing the phenotype). These occurrences are a key challenge for understanding how genetic variants are manifested as human traits –– and a major practical caveat for prognosis of an individual’s disease outcome (or response to a drug or environmental toxicant), based on their genetic data.

However, the causes and mechanisms of variable penetrance are poorly understood. In addition to environmental modifiers (i.e. epigenetics, endogenous influences, environmental agents, or each person’s microbiome) of genetic effects, a potential cause of variable penetrance also might involve other genetic variants having additive (gene-dose) or epistatic (gene x gene interaction) modifier effects. Some studies have successfully mapped genetic modifiers (e.g. BRCA variants in breast cancer; RETT variants in Hirschsprung’s disease).

Yet, genome-wide analysis of pairwise interactions between variants has proven to be challenging in humans. In part, this is because exhaustive pairwise testing of genome-wide interactions typically lacks sufficient statistical power and is easily affected by confounders. Also, a targeted analysis of a specific variant or gene that is strongly implicated in a rare disease typically suffers from a low number of carriers. Nonetheless, emerging large data sets –– with functional genomic and genetic data from disease cohorts –– now enable genome-wide studies of mechanistically justified hypotheses of how combinations of genetic variants might have joint effects on disease risk, drug efficacy, or risk of toxicity to a drug or environmental toxicant.

Coding variants (i.e. nucleotide changes that alter an amino acid) represent many of the strongest associations between genotype (DNA sequence changes) and phenotype; however, coding variants exhibit interindividual differences in effect (variable penetrance). Authors [see attached article] studied how cis-regulatory variation (“cis” refers to effects of nucleotides near the gene –– in contrast to “trans” referring to effects of nucleotides hundreds of thousands of base-pairs distant, or on other chromosomes) modifies the penetrance of coding variants, using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx),

Authors found that, in the general population, purifying selection has depleted haplotype combinations (group of alleles, along any contiguous DNA segment, in an individual that is inherited together from a single parent.) –– that had been predicted to increase pathogenic coding-variant penetrance. Conversely, in cancer and autism spectrum disorder (ASD) patients, authors observed an enrichment of penetrance that increased haplotype configurations for pathogenic variants in disease-implicated genes. These data provide credible evidence that regulatory haplotype configuration of coding variants affects disease risk. Lastly, authors experimentally validated this model by editing a Mendelian single-nucleotide variant (SNV), using CRISPR/Cas9 editing on distinct expression haplotypes with the transcriptome as a phenotypic readout. Their results demonstrated that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants. (As discussed several times previously in these GEITP pages, genetic architecture refers to the underlying genetic basis of any trait. Also called the ‘genotype-phenotype map’, genetic architecture includes EVERYTHING that can possible contribute to the phenotype –– epistasis, polygeny, pleiotropy, quasi-continuity, modularity, phenotypic plasticity, robustness, and evolvability.)

Nature Genet Sept 2o18; 50: 1327–1334

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