Opportunities and challenges for the use of common controls in sequencing studies

Genome-wide association studies using large-scale genome and exome sequencing data have become increasingly valuable in identifying associations between genetic variants and disease, transforming basic research and translational medicine. However, …

Summix: A method for detecting and adjusting for population structure in genetic summary data

Publicly available genetic summary data have high utility in research and the clinic, including prioritizing putative causal variants, polygenic scoring, and leveraging common controls. However, summarizing individual-level data can mask population …


Genome Sequencing Program


Rare variant association tests using external control data from genetic databases


Estimating ancestry proportions from genetic summary data

Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.