Notable Genomics Research

We prioritized 57 druggable targets from 212 putative causal genes of metabolic-dysfunction-associated steatotic liver disease (MASLD). Using a drug-repurposing analysis that integrated protein structural modeling with Mendelian randomization of predicted gene expression, we identified icosapent ethyl and fingolimod as MASLD therapeutic candidates that act via FADS1 and S1PR2 activation.

The use of genomic testing for diagnostic purposes has increased as the cost of sequencing has decreased. However, genomic testing has been deployed mostly in pediatric settings with information on how it can benefit adult populations lacking. In this issue, Gold et al. assess the utility of sequencing for diagnostic purposes in a young adult (ages 18–40) population admitted to the intensive care unit (ICU). Through whole-exome sequencing, the authors discovered 24.4% of the 365 individuals in the cohort had a diagnostic variant.

(The American Journal of Human Genetics 109, 1867–1884; October 6, 2022)

We developed an imputation panel for Alzheimer disease and related dementias (ADRD) using 15,958 whole-genome sequencing samples. Recognizing the significant associations between structural variants (SVs) and AD and their underrepresentation in existing public reference panels, our panel uniquely integrates single-nucleotide variants, short insertions or deletions, and SVs.

Aggregation tests were developed to increase power to detect associations with rare variants. Bose et al. investigate a range of genetic models and sample sizes and demonstrate how sample size × heritability, proportion of causal variants, and choice of mask determine when aggregation tests are more powerful than single-variant tests.

Polygenic risk scores (PRSs) performed best among Hispanics/Latinos with Mainland heritage that can be traced back to Mexico, and Central and South Americas. Incorporating functional annotations improved PRS performance in those with greater African admixture, as occurs with Caribbean heritage, highlighting the importance of ancestry-specific considerations in PRS development for diverse Hispanic/Latino populations.

Disruptions in cohesin or its regulators, including CHTF18, can lead to a diverse group of cohesinopathies. We identified and described several individuals with rare missense variants in CHTF18 and neurodevelopmental and congenital phenotypes. The function, relevance, and pathway involvement of CHTF18 make it a promising candidate gene.

Benchmarking of SHAPEIT and Beagle phasing methods on 23andMe’s 8.6 million research-consented dataset reveals extraordinarily low error rates. We also introduce HAPTiC, a novel inter-chromosomal phasing method using IBD segments. Overall, we demonstrate that IBD coverage is crucial for accurate haplotype phasing across diverse populations.

This study systematically characterized TP53 variants with reduced penetrance, revealing intermediate functional effects and later-onset cancer risk compared with classic pathogenic variants. Using a random forest predictive model, we identified novel candidate reduced penetrance variants, which has important clinical implications for management of cancer patients with these variants.

We report that genetic predisposition influencing serum immunoglobulin E (sIgE) levels is associated with the development of allergies in children, including food allergy and atopic dermatitis. Polygenic scores for sIgE may help identify children at high genetic risk, enabling early intervention to reduce allergy-related disease burden.

We report on an international survey of health data ecosystems (HDEs) based on live interviews with project leaders in a dozen countries. The remarkable diversity of HDEs works against collective actions like international data sharing while spurring much-needed research on how to measure the comparative success of individual HDEs.

We present a method that combines inferred gene genealogical trees with local ancestry calls to estimate ancestry-specific expected genetic relationship matrix (as-eGRM) for admixed populations. Extensive evaluation shows that as-eGRM improves the inference of fine-scale substructure within ancestry components and the correction of population stratification in genome-wide association studies.

This study benchmarks polygenic scoring methods across ancestrally diverse populations and introduces a summary-statistic-based strategy for optimally combining population-specific scores. The findings support flexible, efficient, and equitable genomic prediction using multi-ancestry GWASs, with all methods implemented in the open-source GenoPred pipeline.

CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aimed to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures, and explore potential genotype-phenotype correlations.

Biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset colorectal cancer, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts.