# Population genetics for large-scale sequencing studies of diverse populations

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $558,911

## Abstract

Summary
Population-based studies identifying the genetic variants that affect complex human diseases have relied
heavily on population-genetic principles in important tasks such as study design, quality control, and genotype
imputation. The dramatic growth of large-scale genotyping and sequencing studies of disease generates new
challenges both for modeling the underlying generative population-genetic processes that give rise to evidence
of disease association in data sets and for performing statistical analysis to uncover disease variants. These
challenges magnify the potential for approaches grounded in population genetics to maximize the return from
ongoing investigations. Because studies thus far have often focused on populations of European descent, it is
critical that new methods provide tools for a greater diversity of populations. This project builds on productive
efforts in two previous funding periods, capitalizing on the study of human population genetics to enhance the
design, analysis, and interpretation of genomic studies of disease. It exploits the fundamental principle of
human genetics that population-genetic phenomena are responsible for homozygous placement of recessive
risk variants, and the recent recognition that accumulations of runs of homozygosity (ROH), and hence, of
multiple recessive deleterious variants of small effect in homozygous form, can contribute to disease risk.
Particularly for large-scale genotyping and low-coverage sequencing studies, in which rare recessive variants
are difficult to analyze, this project uses the population genetics of ROH to enhance discovery. The project
expands beyond the setting of rare diseases in small populations, building on observations that ROH and
accumulations of recessive deleterious variants of small effect contribute to complex disease risk in outbred
groups, including admixed populations. (1) We will construct models of the effects of interacting population-
genetic forces on ROH. Such models will make it possible for researchers to attribute ROH patterns to effects
of inbreeding, population size history, admixture, and selection against deleterious recessive variants. (2) We
will develop powerful new tests that measure effects of ROH on complex disease risk. These tests will employ
population-genetic models that incorporate features of genetic architecture and genomic parameters to assess
if associations between ROH and disease reflect the likely presence of recessive disease variants. (3) We will
differentiate between germline and somatically acquired homozygosity, leveraging signals in intermediate data
types and genotype distributions from population genetics, to identify false-positive ROH and to refine
detection of chromosomal alterations. (4) We will comprehensively evaluate the impact of ROH on medical
traits in multiple disease studies, using the Michigan Genomics Initiative and UK Biobank to test and inform our
approaches. The application of association testing be...

## Key facts

- **NIH application ID:** 10518819
- **Project number:** 2R01HG005855-11
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Noah Rosenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $558,911
- **Award type:** 2
- **Project period:** 2010-09-13 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518819

## Citation

> US National Institutes of Health, RePORTER application 10518819, Population genetics for large-scale sequencing studies of diverse populations (2R01HG005855-11). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10518819. Licensed CC0.

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