遗传关联分析 77,539 基因组揭示罕见疾病病因.

The genetic etiologies of more than half of rare diseases remain unknown.
Standardized genome sequencing and phenotyping of large patient cohorts
provide an opportunity for discovering the unknown etiologies, but this
depends on efficient and powerful analytical methods. We built a compact
database, the ‘Rareservoir’, containing the rare variant genotypes and
phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project.
We then used the Bayesian genetic association method BeviMed to infer
associations between genes and each of 269 rare disease classes assigned by
clinicians to the participants. We identified 241 known and 19 previously
unidentified associations. We validated associations with ERG, PMEPA1 and
GPR156 by searching for pedigrees in other cohorts and using bioinformatic
and experimental approaches. We provide evidence that (1) loss-of-function
variants in the Erythroblast Transformation Specific (ETS)-family
transcription factor encoding gene ERG lead to primary lymphoedema, (2)
truncating variants in the last exon of transforming growth factor-β
regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function
variants in GPR156 give rise to recessive congenital hearing impairment.
The Rareservoir provides a lightweight, flexible and portable system for
synthesizing the genetic and phenotypic data required to study rare disease
cohorts with tens of thousands of participants.