Genome-wide association studies (GWAS) traditionally assume an additive model of genetic inheritance, where the genetic effect of a heterozygous genotype is exactly intermediate to the genetic effects of the two homozygous genotypes. However, we know that many alleles act in either a dominant or recessive fashion. Detecting the phenotypic effects of rare, recessive variants is especially challenging, due to the scarcity of rare, homozygous genotypes. Here, we propose to use data from 96,000 individuals from the Pakistan Genomic Resource (PGR) to quantify the effects of rare, recessive variants on a wide range of phenotypic traits and common, complex diseases. Our study leverages the high rates of inbreeding within the PGR (which increases the frequency of rare, homozygous genotypes), as well as extensive lifestyle, family history and genetic data from all participants.
The specific aims for our project are (1) Phase and impute variants into more than 96,000 PGR genomes using a reference panel that includes 6,200 high- coverage genome sequences from South Asia; (2) Test for associations between a wide range of phenotypes and genotype, using a combination of standard single-variant tests and novel homozygosity-mapping approaches; and (3) Infer historical models of consanguinity within the PGR, using the distributions of long runs of homozygosity (caused by consanguineous marriages) both within and between individuals.

Public Health Relevance

The Pakistan Genomic Resource (PGR) is a unique cohort of individuals with extensive phenotypic data and high rates of consanguinity. We plan to leverage these attributes, along with the availability of genome-wide genotype data from PGR samples, to discover novel genetic variants that can help predict disease susceptibility and help improve our understanding of the genetic contributions to medically relevant biomarkers such as blood pressure and cholesterol levels.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
1R01HG010689-01
Application #
9803204
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Li, Rongling
Project Start
2019-09-13
Project End
2023-06-30
Budget Start
2019-09-13
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118