154: Multiple-testing corrections in IBD-based selection scans

Temple SD et al., The American Journal of Human Genetics - Temple and Browning model correlations of identity-by-descent (IBD) rates to derive analytical and simulation-based genome-wide significance thresholds for selection scans, apply these to TOPMed and UK Biobank cohorts, and show many signals cluster near structural-variant hotspots. Key terms: identity-by-descent, selection scans, multiple testing, Ornstein-Uhlenbeck, population genetics.

Study Highlights:
The authors model standardized IBD rates along chromosomes as an Ornstein-Uhlenbeck process to obtain analytical and simulation-based multiple-testing thresholds that account for test spacing. In whole-genome simulations the methods approximately control the family-wise error rate, with the ≽5.3 cM scan tending toward anti-conservative behavior and the ≽6.3 cM scan conservative. Power exceeds 50% for hard sweeps with selection coefficients ≥0.01 at intermediate present-day allele frequencies. Applying the corrected thresholds to TOPMed and UKBB reduced the number of candidate loci and revealed shared excess-IBD regions enriched for structural variants.

Conclusion:
Modeling genomic autocorrelation of IBD rates yields practical multiple-testing corrections that reduce false positives in recent-selection scans, but interpretation must consider structural variation, demographic effects, and limitations of the OU approximation.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Multiple-testing corrections in selection scans using identity-by-descent segments

First author:
Temple SD

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.09.004

Reference:
Temple SD, Browning SR. Multiple-testing corrections in selection scans using identity-by-descent segments. Am J Hum Genet. 2025;112:1–21. doi:10.1016/j.ajhg.2025.09.004

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/multiple-testing-corrections-in-selection-scans-using-identity-by-descent-segments

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-10-01.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing the OU process modeling of IBD rates, the analytical Siegmund–Yakir approximation, the simulation-based thresholds, the power for hard sweeps, and the empirical findings including LCT, OCA2, HBB signals and the structural-variant mirages near XYLT1 and 22q11.21.
- transcript topics: Genome pattern recognition and IBD sharing; Identity-by-descent segments and selection scans; Multiple-testing corrections and FWER; Ornstein–Uhlenbeck process modeling of IBD rates; Analytical (Siegmund–Yakir) and simulation-based thresholds; Power to detect hard sweeps

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Model OU process to derive genome-wide significance for IBD-based scans
- Analytical Siegmund–Yakir approximation and simulation-based thresholds
- Power to detect hard sweeps with s >= 0.01 at intermediate allele frequencies
- LCT, OCA2, HBB signals observed across ancestries
- Cross-ancestry signals and structural-variant confounds near XYLT1 and 22q11.21
- Call for adopting OU-based thresholds and recognizing model limitations in founder/panmictic vs structured populations

QC result: Pass.