Multiple-testing corrections in case-control studies using identity-by-descent segments

Topic: Risk, prevention and care in population studies

Identity-by-descent (IBD) mapping provides complementary signals to genome-wide association studies (GWASs) when multiple causal haplotypes or variants are present but not directly tested. We propose the difference between affected-affected and control-control IBD rates as an IBD mapping statistic. For our hypothesis test, we use a computationally efficient approach from the stochastic processes literature to derive genome-wide significance levels that control the family-wise error rate (FWER). Whole-genome simulations indicate that our method conservatively controls the FWER. We pair our IBD mapping approach with a selection scan and a validation procedure via phenotype randomization so that one can contrast results for evidence of confounding due to positive selection, sequencing artifacts, or population structure. We developed automated and reproducible workflows to phase haplotypes, call local ancestry probabilities, and perform the IBD mapping scan, the former two tasks being important preprocessing steps for haplotype analyses. We applied our methods to search for Alzheimer disease (AD) risk loci in the Alzheimer's Disease Sequencing Project (ADSP) genome data. We identified six genome-wide significant signals of AD risk among samples genetically similar to African and European reference populations and self-identified Amish samples. Some variants in the six risk loci we detected have previously been associated with AD, dementia, and memory decline, and four genes at two of these loci have already been nominated as therapeutic targets for AD. Overall, our scalable approach makes further use of large consortia resources, which are expensive to collect but provide insights into disease mechanisms.

Key findings

• Whole-genome simulations indicate that our method conservatively controls the FWER.
• We pair our IBD mapping approach with a selection scan and a validation procedure via phenotype randomization so that one can contrast results for evidence of confounding due to positive selection, sequencing artifacts, or population structure.
• We identified six genome-wide significant signals of AD risk among samples genetically similar to African and European reference populations and self-identified Amish samples.
• Some variants in the six risk loci we detected have previously been associated with AD, dementia, and memory decline, and four genes at two of these loci have already been nominated as therapeutic targets for AD.
• Overall, our scalable approach makes further use of large consortia resources, which are expensive to collect but provide insights into disease mechanisms.

Why it matters

This methods paper describes a new identity-by-descent mapping approach for finding Alzheimer's disease risk loci and identified six genome-wide significant signals in African, European, and Amish samples. It is a statistical genetics method and does not test or propose a treatment, cure, or prevention.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.ajhg.2026.01.013
• PubMed: 41709460
• Original source →
• Free full text: The American Journal of Human Genetics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{temple2026-41709460,
  author  = {Temple, Seth D and Chapman, Nicola H. and Choi, Seung Min and DeStefano, Anita L. and Thornton, Timothy A. and Wijsman, Ellen Marie and Blue, Elizabeth},
  title   = {{Multiple-testing corrections in case-control studies using identity-by-descent segments}},
  journal = {The American Journal of Human Genetics},
  year    = {2026},
  doi     = {10.1016/j.ajhg.2026.01.013},
  pmid    = {41709460},
  url     = {https://doi.org/10.1016/j.ajhg.2026.01.013}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics JAMA · 1998-03-01 · usefulness score 70/100 · Genetics
• The complex genetic architecture of Alzheimer's disease: novel insights and future directions EBioMedicine · 2023-03-10 · usefulness score 58/100 · Inflammation and the immune system
• Genome-wide interaction analysis of pathological hallmarks in Alzheimer's disease Neurobiology of aging · 2020-04-29 · usefulness score 49/100 · Long-term cohort studies

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• Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study PLoS medicine · 2017-03-28 · usefulness score 64/100
• Risk factors for dementia with Lewy bodies: a case-control study Neurology · 2013-07-26 · usefulness score 58/100
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• Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report Nature medicine · 2019-11-04 · usefulness score 52/100

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