Research articles

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Recurrent de novo mutations at nucleotide positions 4 and 35 of RNU2-2 cause a neurodevelopmental disorder whose prominent features include intellectual disability, developmental delay and a complex seizure phenotype.

Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.

Tumor cells upregulate compensatory buffering genes following tumor suppressor loss. These genes may represent new synthetic lethal partners that could be harnessed therapeutically.

Histologically normal tissues of individuals with a germline NF1 mutation exhibited multiple second NF1 hits, unrelated to their tumors, that conferred a selective advantage.

SF-GWAS is a workflow for secure, federated genome-wide association studies, implementing accurate, privacy-preserving principal-component analysis, linear/logistic regression and linear mixed model methods for biobank-scale multisite analyses.

Genome-wide and multitrait analyses identify novel loci associated with hypertrophic cardiomyopathy and relevant left ventricular traits. Gene-level burden analyses show that rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy.

A novel in vivo screening strategy identifies new modifiers of somatic CAG repeat expansion that contribute to age of onset in Huntington’s disease.

Genome-wide association and multitrait analyses for dilated cardiomyopathy (DCM) using 9,365 cases and 946,368 controls provide insights into the mechanisms underlying DCM and myocardial resilience

Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.

Genome-wide analyses identify variants in B3GALT5 and ST6GAL1 associated with influenza susceptibility. Knockdown of ST6GAL1 in cell culture reduces influenza infectivity, likely by interfering with the glycoprotein modifications required for viral entry.

Genomic analysis identifies an SVA retrotransposon insertion in an intron of ASIP as a likely causal variant influencing human pigmentation. This insertion appears to mitigate the effects of an older, nonpolymorphic SVA insertion in the same intron.

Marker-based CRISPR screens in pancreatic cancer cells followed by functional validation highlight a role for MED12 in bridging ΔNp63 and components of the Mediator family. This interaction helps drive basal cell identity in pancreatic ductal adenocarcinoma.

Analysis of exome sequencing data identifies a missense variant in RAB32 associated with high risk of familial Parkinson’s disease. Functional studies show that this risk variant increases LRRK2 kinase activity.

Long-read sequencing identifies a GGC-repeat expansion in the coding region of ZFHX3 as the cause of spinocerebellar ataxia type 4. The expansion encodes polyglycine and results in intranuclear aggregates and abnormal autophagy.

Genome-wide association analyses identify 13 loci associated with gestational diabetes, showing partial overlap with type 2 diabetes risk loci but also distinct genetic architecture predominantly influencing pregnancy-related mechanisms.

Neural networks are a common machine learning architecture for predicting phenotype from genomic sequence. This analysis finds that they err in calling the variant direction of effect, with important implications for personalized predictions.

Loss-of-function mutations in primate-specific ZNF808 cause pancreatic agenesis. Mechanistically, the loss of ZNF808 leads to the activation of the MER11 family of transposable elements in a regulatory capacity that ultimately induces a liver-specific program of gene expression during pancreatic differentiation.

A multi-ancestry genome-wide association study of prostate cancer performed in 156,319 cases and 788,443 controls identifies 187 novel risk variants associated with the disease. Genetic risk scores associated with overall risk, and risk of aggressive disease in men of African ancestry.

The mitochondrial transcription factor A is excluded from the mitochondria in spermatozoa by virtue of phosphorylation of the mitochondrial presequence. This is associated with transport to the nucleus and loss of mitochondrial DNA (mtDNA) from the mitochondria, providing a mechanistic basis for uniparental inheritance of mtDNA in humans.