Evaluating the Potential of Younger Cases and Older Controls Cohorts to Improve Discovery Power in Genome-Wide Association Studies of Late-Onset Diseases

Abstract

For more than a decade, genome-wide association studies have been making steady progress in discovering the causal gene variants that contribute to late-onset human diseases. Polygenic late-onset diseases in an aging population display a risk allele frequency decrease at older ages, caused by individuals with higher polygenic risk scores becoming ill proportionately earlier and bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population. This phenomenon is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes, while for late-onset diseases with relatively lower prevalence and heritability, exemplified by cancers, the effect is significantly lower. In this research, computer simulations have demonstrated that genome-wide association studies of late-onset polygenic diseases showing high cumulative incidence together with high initial heritability will benefit from using the youngest possible age-matched cohorts. Moreover, rather than using age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

The genetic consequences of dog breed formation—Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels

“…As a further means to increase the discovery power for a late-onset, polygenic disease, such as MMVD, we next investigated whether genotype alone can predict simple disease status in samples including only young cases and old controls [ 42 ]. For this purpose, we genotyped all candidate variants in 26 additional dachshunds belonging to a retrospectively sampled Danish cohort [ 43 , 44 ].…”

“…Consistent with this, univariate analysis showed that NEBL 2 genotype predicted MMVD in subsamples of the dachshund population that only included increasingly young affected individuals and increasingly old healthy controls, but not in the complete dachshund population (age range: 5–16 years). Comparisons of young cases and old controls will increase discovery power for late onset polygenic diseases, such as MMVD, [ 42 ] as it removes biases introduced by i ) risk allele carriers that are too young to have started expressing signs of disease, ii ) old cases in which MMVD partly may have been triggered by mechanical wear rather than high polygenic risk and iii ) a paucity of old risk allele carriers due to premature deaths associated with the disease [ 52 ]. Congruent with a potential link between regulatory NEBL variants and MMVD we also note that the derived NEBL 1 allele predicted echocardiographic signs of MMVD using univariate analysis in a small Swedish beagle population (n = 22).…”

Combination of HLA-DQ2/-DQ8 Haplotypes and a Single MSH5 Gene Variant in a Polish Population of Patients with Type 1 Diabetes as a First Line Screening for Celiac Disease?

“…The study cohort consisted of 248 T1D pediatric patients under 18 years old (median age 8; 137 females and 111 males), 287 pediatric patients with recognized CD under 18 years (median age 4; 185 females and 102 males), and 551 healthy individuals recruited from Polish blood donors for other GWAS projects (median age 28 years; 403 females and 148 males). The control group was older than the CD and T1D groups, however, according to recently published analyses showing that study cohorts combining the younger cases with the older controls may significantly improve the discovery power of GWAS [16], the age of the groups in our study should not affect the obtained results.…”