Challenges of Linkage Analysis in the Era of Whole‐Genome Sequencing

Abstract

Whole-genome sequencing (WGS) is becoming an affordable technology for the study of the genetics of complex traits. With any new technology, experimental designs and statistical methods, both old and new, must be evaluated. One design seeing a resurgence of interest is the use of families. Genetic Analysis Workshop 18 provided the opportunity to evaluate statistical methods applied to WGS data for family-based studies. We summarize the results of five contributions that used linkage in the context of WGS. The investigators took differing approaches, including assessment of false-positive rates in classic two-point linkage, the effects of heterogeneity on linkage and association tests, and the use of linkage to focus association tests. We describe the primary findings of each contribution and note challenges that are not new to those working in family designs or specific to WGS data; for example, choice of phenotype definition, covariate adjustment, and use of longitudinal data may produce different results, making comparisons challenging. We detail new issues brought about by WGS, such as the elevated genome-wide false-positive rate for classic two-point parametric linkage analysis, computational demands in multipoint calculations, and lack of clarity in how to best use linkage to focus association testing. Finally, we comment on when linkage may be helpful for WGS, highlighting where additional research is needed; for example, although linkage analysis has been successful in the study of rare variants of large effect, how to best use family information in the context of rare variants of moderate effect remains an open research question.

Identification of rare variants in Alzheimer’s disease

“…Another potential way to enrich subjects for genetic risk factors is to utilize individuals with a strong family history of the condition, since pedigrees with multiple affected individuals are more likely to have pre-disposing genetic variants than typical sporadic cases. Indeed, the way in which traditional genetic linkage approaches can be effectively used in conjunction with new technological and analytical methods for the identification of rare, disease causing mutations is currently being explored ( Santorico and Edwards, 2014 ).…”

PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

“…Today, investigators continue to use pedigrees to determine the heritability and genetic models for traits and disorders, and knowing the exact pedigree structure allows them to correctly identify the genetic mode of disease inheritance and utilize powerful genetic-analysis tools that require, or benefit from, the true pedigree structure. Such tools include linkage, 1 family-based association, 2 pedigree-aware imputation, pedigree-aware phasing, Mendelian error checking, heritability, and pVAAST (Pedigree Variant Annotation, Analysis, and Search Tool). 3 In many instances, knowing the pedigree that is consistent with the generated genetic data is crucial to solving the disease.…”

Profiling and leveraging relatedness in a precision medicine cohort of 92,455 exomes

“…Third, families who 9 have visited a healthcare system for many years with multiple encounters will have 10 extensive medical records, making them more likely to be included in a study compared 11 to transient residents with brief medical records and fewer encounters. Both family 12 structure and distant cryptic relatedness are more pronounced in populations with low 13 migration rates 5 . Conversely, confounding population substructure may be less of a factor 14 in HPG studies if the sampled healthcare system's population is a single homogenous 15 genetic deme 1 .…”

“…5 We show that cryptic family structure in a large sequencing dataset presents an 6 opportunity to harness a valuable, untapped source of genetic insights rather than a 7 nuisance that must be managed during downstream analyses. As we enter the era of 8 genomic-based precision medicine, we see a critical need for additional innovative 9 methods and tools that are capable of effectively mining the familial structure and distant 10 relatedness contained within the ever-growing sequencing cohorts.…”

“…We reconstructed 12,574 pedigrees using these relationships 4 (including 2,192 nuclear families) and leveraged them for multiple applications. The 5 pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious 6 compound heterozygous mutations. Reconstructed nuclear families were critical for 7 identifying 3,415 de novo mutations in ~1,783 genes.…”