Disease‐Concordant Twins Empower Genetic Association Studies

Abstract

Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient population. Simulation was done by assigning various allele frequencies and allelic relative risks for different mode of genetic inheritance. In general, for achieving a power estimate of 80%, the sample sizes needed for dizygotic and monozygotic twin cases were one half and one fourth of the sample size of an ordinary case-control design, with variations depending on genetic mode. Importantly, the enriched power for dizygotic twins also applies to disease-concordant sibling pairs, which largely extends the application of the concordant twin design. Overall, our simulation revealed a high value of disease-concordant twins in genetic association studies and encourages the use of genetically related individuals for highly efficiently identifying both common and rare genetic variants underlying human complex diseases without increasing laboratory cost.

Heritability and Genome-Wide Association Analyses of Serum Uric Acid in Middle and Old-Aged Chinese Twins

“…Phenotype variation may be under the effect of subjects’ genetic background, age, gender, and environmental exposures as well as some experimental variables related to sampling, processing, and data analysis. Genetically related individuals, such as twin pairs, would highly confer increased power in genetic association analysis and efficiently identify genetic variants underlying human complex diseases ( 20 ). Second, given the various genetic constitutions and multitude of life style among different ethnic populations in the world, this is the first GWAS conducted in the sample of middle and old-aged Chinese twins.…”

“…Chinese population differs in the genetic constitutions and a multitude of life style like dietary habit, work type, and physical activity from other ethnic populations in the world. Genetically related individuals, such as twin pairs, would highly confer increased power in genetic association analysis and efficiently identify genetic variants underlying human complex diseases ( 20 ).…”

A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

“…We do, however, realize that other annotation methods, for instance considering the trans regulatory roles of the CpGs, could give different results and consequently give rise to different sets of overlapping genes. One important strength of this study is the use of twin pairs; the intra-pair EWAS and TWAS enable us to explore genes associated with epigenetic or transcriptomic variation and cognition independent of genetic background and sheared early environment (Tan et al, 2015), significantly increasing the power of the study (Tan et al, 2017). Furthermore, as the correlation of cognitive functioning between the twins of a pair has been reported to decline with age, indicating that non-shared environmental and stochastic effects accumulate across lifespan potentially influencing the levels of cognitive functioning in aging individuals (McCartney et al, 1990), it supports the use of middle-aged and old-aged twins for studying the contribution of epigenetic and transcriptomic variation to the variation in cognitive functioning in later life.…”

Post-traumatic Stress Disorder Symptoms are Associated With Incident Chronic Back Pain

“…Restriction to twin pairs concordant for absence of disease may define a baseline study sample that is enriched for those genetically predisposed to not having a particular disease, 53 Strengths of the current study include the longitudinal design, the unique ability of the co-twin control design to adjust for genetics and early family environment, and the use of accepted and validated measures for PTSD symptoms 37 and back pain. 39 Potential limitations include the use of surveys to ascertain CBP status, rather than structured interviews, and the reliance on recalled pain, the accuracy of which decreases according to the length of the recall period.…”