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Waller et al. J Transl Genet Genom 2021;5:112-23 Journal of Translational
DOI: 10.20517/jtgg.2021.09 Genetics and Genomics

Original Article Open Access

Duo Shared Genomic Segment analysis identifies
a genome-wide significant risk locus at 18q21.33 in

myeloma pedigrees

Rosalie Griffin Waller 1,2,3 , Michael J. Madsen , John Gardner , Douglas W. Sborov , Nicola J. Camp 1,2
1,2
1
1
1 Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
2 University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
3 Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
Correspondence to: Dr. Nicola J. Camp, Huntsman Cancer Institute, 2000 Circle of Hope, Rm 4757, Salt Lake City, UT 84112,
USA. E-mail: Nicki.Camp@hci.utah.edu

How to cite this article: Waller RG, Madsen MJ, Gardner J, Sborov DW, Camp NJ. Duo Shared Genomic Segment analysis
identifies a genome-wide significant risk locus at 18q21.33 in myeloma pedigrees. J Transl Genet Genom 2021;5:112-23.
http://dx.doi.org/10.20517/jtgg.2021.09
Received: 2 Mar 2021 First Decision: 13 Apr 2020 Revised: 13 Apr 2020 Accepted: 26 Apr 2021 Available online: 27 May 2021

Academic Editor: Susan L. Slager Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

Abstract
Aim: High-risk pedigrees (HRPs) are a powerful design to map highly penetrant risk genes. We previously described
Shared Genomic Segment (SGS) analysis, a mapping method for single large extended pedigrees that also
addresses genetic heterogeneity inherent in complex diseases. SGS identifies shared segregating chromosomal
regions that may inherit in only a subset of cases. However, single large pedigrees that are individually powerful
(at least 15 meioses between studied cases) are scarce. Here, we expand the SGS strategy to incorporate evidence
from two extended HRPs by identifying the same segregating risk locus in both pedigrees and allowing for some
relaxation in the size of each HRP.

Methods: Duo-SGS is a procedure to combine single-pedigree SGS evidence. It implements statistically rigorous
duo-pedigree thresholding to determine genome-wide significance levels that account for optimization across
pedigree pairs. Single-pedigree SGS identifies optimal segments shared by case subsets at each locus across
the genome, with nominal significance assessed empirically. Duo-SGS combines the statistical evidence for SGS
segments at the same genomic location in two pedigrees using Fisher’s method. One pedigree is paired with all
others and the best duo-SGS evidence at each locus across the genome is established. Genome-wide significance
thresholds are determined through distribution-fitting and the Theory of Large Deviations. We applied the duo-
SGS strategy to eleven extended, myeloma HRPs.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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