Data from: A variant in the 5′UTR of ERBB4 is associated with lifespan in Golden Retrievers

Genome-wide association studies (GWAS) in long-lived human populations
have led to identification of variants associated with Alzheimer’s disease
and cardiovascular disease, the latter being the most common cause of
mortality in people worldwide. In contrast, naturally occurring cancer
represents the leading cause of death in pet dogs, and specific breeds
like the Golden Retriever (GR) carry up to a 65% cancer-related death
rate. We hypothesized that GWAS of long-lived GRs might lead to the
identification of genetic variants capable of modifying longevity within
this cancer-predisposed breed. A GWAS was performed comparing GR
dogs ≥ 14 years to dogs dying prior to age 12 which revealed a
significant association to ERBB4, the only member of the epidermal growth
factor receptor family capable of serving as both a tumor suppressor gene
and an oncogene. No coding variants were identified, however, distinct
haplotypes in the 5′UTR were associated with reduced lifespan in two
separate populations of GR dogs. When all GR dogs were analyzed together
(n = 304), the presence of haplotype 3 was associated with shorter
survival (11.8 years vs. 12.8 years, p = 0.024). GRs
homozygous for haplotype 3 had the shortest survival, and GRs homozygous
for haplotype 1 had the longest survival (11.6 years vs.
13.5 years, p = 0.0008). Sub-analyses revealed that the
difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was
specific to female dogs (p = 0.009), whereas survival remained
significantly different in both male and female GRs homozygous for
haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken
together, these findings implicate a potential role for ERBB4 in GR
longevity and provide evidence that within-breed canine lifespan studies
could serve as a mechanism to identify favorable or disease-modifying
variants important to the axis of aging and cancer.