Michael E. Talkowski

Genetic and Epigenetic Landscape of Self-Identified Hispanics/Latino in All Of Us

The paper analyzes genetic variation, ancestry, and DNA methylation in Hispanic/Latino participants using long-read sequencing, identifying novel variants and phenotype associations.

Multi-omics in the All Of Us Research Program expands mapping genetic mechanisms in health and disease

The paper reports on the All of Us multi-omics cohort, identifying 182,246 QTLs and demonstrating rare variant effects across proteomic and transcriptomic data.

Tandem repeat variation shapes immune cell type-specific gene expression

The paper identifies immune cell type-specific gene expression regulated by tandem repeats using multi-omics data from large cohorts.

Characterization of de novo structural variants in trios with orofacial clefts

This study identifies de novo structural variants in individuals with orofacial clefts and finds they contribute to genetic risk, with some variants disrupting known risk genes and suggesting new candidate genes.

Perisynaptic matrix gene variants underlie DystoniaGeneNet endophenotypes in isolated focal dystonia

This paper uses a deep learning model to identify genetic variants associated with isolated focal dystonia by leveraging neuroimaging endophenotypes.

Large language model classifies prior evidence in gene-phenotype associations

PESTO classifies gene-phenotype associations as Novel, Hypothesized, Existing, or Established using a large language model and structured genetic evidence, identifying 7% as Novel and 21% as Hypothesized in 940 associations.

Phenotypic structure and genetic correlates of adolescent psychiatric symptomatology in versus out of autism

The paper compares the phenotypic and genetic structures of psychiatric symptoms in autistic and non-autistic children, finding differences in factor structures and genetic associations.

Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders

The paper identifies rare variants in CSMD2 associated with neurodevelopmental disorders, showing both recessive and dominant inheritance patterns and functional impairments.

Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations

Autism genes converge on three functional programs organized by neuronal subclass, developmental timing, and cortical patterning

This study identifies three functional programs impacted by autism genes, contextualized across neuronal subclasses, developmental timing, and cortical regions.

Genomic Research as a Critical Pathway to Diagnosis for Individuals with Rare Disease

The Rare Genomes Project provides remote genomic sequencing to rare disease families, achieving a 23.3% diagnostic solve rate and highlighting the role of research in overcoming clinical diagnostic barriers.

Estimating the contribution of coding mutations to autism

The paper estimates the contribution of de novo coding mutations to autism using data from 38,680 trios, finding they explain 3.4% of autism variance.

Rare variation illuminates the distinct and pleiotropic genetic architecture of autism across neuropsychiatric traits

The paper identifies 253 autism-associated genes using rare variation from 62,429 individuals and finds pleiotropy across physiological systems and developmental disorders.

A high-resolution human pangenome structural variant resource for improved disease association

The paper constructs a high-resolution human pangenome structural variant resource, identifies disease-associated SVs, and demonstrates its utility in filtering variants from probands and associating SVs with traits in a large cohort.

A global view of human centromere variation and evolution

The paper assembles and characterizes 2,110 human centromeres, revealing novel haplotypes, mobile element insertions, and mutation rate variation across chromosomes.

CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling

The paper investigates how POGZ loss-of-function affects transcription factor binding and gene expression in neurons, revealing shared molecular changes with other NDD-related genes.

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing

This study evaluates the diagnostic yield of short-read and long-read sequencing in rare diseases, finding limited added value from long-read sequencing despite increased variant discovery.

Comprehensive analysis of de novo variants across 2,497 orofacial cleft trios reveals novel genetic drivers of disease

This study identifies novel genetic drivers of orofacial clefts by analyzing de novo variants in 2,497 trios and integrating findings across subtypes and syndromic status.

Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset

The paper introduces a data model and dataset for rare disease research, enabling interoperable multi-omic data integration across clinical sites.

NeuroDev: etiology and experience of neurodevelopmental disorders in Kenya and South Africa

The paper presents genetic and phenotypic data from 521 children with neurodevelopmental disorders in Kenya and South Africa, highlighting high genetic diagnosis rates linked to environmental risk factors.

Multi-omics profiling reveals MAGEL2-driven defects in human corticogenesis shared across Prader-Willi and Schaaf-Yang syndromes.

This study identifies MAGEL2-driven defects in human corticogenesis shared between Prader-Willi and Schaaf-Yang syndromes using multi-omics profiling of induced neurons.

Convergent coexpression reveals shared biological mechanisms underlying common and rare variant risk in six neuropsychiatric disorders

The paper identifies convergent coexpressed genes shared between common and rare variant risk genes in six neuropsychiatric disorders, revealing shared biological mechanisms and therapeutic targets.

Integrating 730,947 exome sequences with clinical literature improves gene discovery

gnomAD v4 (730,947 exomes) brings LOFTEE-2 loss-of-function annotation (0.90 precision, strict mode), missense-aware constraint, and LLM-mined literature evidence combined with constraint to rank disease genes.

Common and rare variant genetic contributions in African Americans with autism.

This study examines common and rare variant genetic contributions to autism in African Americans, highlighting differences in genetic effects and polygenic score transferability between European and African ancestries.

Large-scale discovery of neural enhancers for cis-regulation therapies

The paper identifies active human neural enhancers and CRISPRa gRNAs that upregulate NDD risk genes, providing a resource for cis-regulatory therapy development.

Population-scale Long-read Sequencing in the All of Us Research Program

The paper analyzes long-read sequencing data from the All of Us Research Program to identify structural variants and their associations with diseases in a large cohort of Black or African American participants.

Aberrant recursive splicing in a human disease locus

The paper investigates the functional role of recursive splicing in CADM2, showing that its deletion leads to altered gene expression and behavioral changes in neurodevelopmental disorders.

Complex genetic variation in nearly complete human genomes

Hybrid HiFi/ultra-long ONT assemblies of 65 diverse humans yield 130 haplotypes, 1,246 complete centromeres, and a pangenome panel enabling short-read genome inference at median QV 45.

Functional consequences of genetic risk for neuropsychiatric conditions at chr22q

The paper identifies chr22q as a regulatory hub where genetic risk for neuropsychiatric conditions is associated with coordinated gene expression downregulation in brain tissue.

Loss of CFHR5 function reduces the risk for age-related macular degeneration

The paper identifies CFHR5 variants that reduce AMD risk by lowering FHR-5 levels and altering complement pathway activity.