Genome‐wide gene‐based analysis of episodic memory trajectories in the Mexican Health and Aging Study (MHAS)

Abstract

AbstractBackgroundUnderstanding genetic modulation of memory will yield insight into the biological mechanisms underlying memory decline and dementia. The cognitive genetics field has largely focused on populations of European descent. Including genetically diverse populations, such as the Mexican population, the largest USA minority group, will increase our understanding of the genetic architecture of memory function.MethodThe analysis sample consisted of 17,650 participants from the Mexican Health and Aging Study for whom socio‐demographic and longitudinal scores on episodic memory were available. Adjusted trajectories of memory performance were estimated using Latent Class Mixed Models. Genome‐wide gene‐based analyses were carried out in the sub‐sample of participants (n = 2,433) with imputed genotyped data (Haplotype Reference Consortium reference). The slope of episodic memory scores was used as the outcome in gene‐based analyses adjusted for sex, age, education, kinship matrix and principal components. Secondary analyses were restricted to participants with Native‐American ancestry (n = 1,842).ResultThe majority of the participants (77%) clustered as Stables, those who maintained their memory performance over time. Compared to those classified within the Stable memory trajectory, the prevalence of dementia was higher among Decliners. Zinc metabolism appear to be essential for neurogenesis, and neural migration and dietary zinc deficiency has been associated with memory impairment. The Zinc Finger CCHC Domain‐Containing Protein 2 (ZCCHC2) gene yielded the strongest association (p = 4.1 × 10−5). A less strong association with ZCCHC2 was also observed (p = 0.003) in the Native‐American ancestry sub‐sample. However, among the Native‐American participants, a different gene yielded the strongest association (p = 1.3 × 10−4), the Intraflagellar Transport 74 (IFT74) gene. The gene is a member of the IFT complex implicated in the vesicular trafficking to axons and dendrites. Sequence variants in IFT74 have been linked to a form of amyotrophic lateral sclerosis accompanied by progressive cognitive impairment.ConclusionGenetic variation influence longitudinal changes in episodic memory in a sample of Mexican population. Our results suggest that the indigenous Native American ancestry of Mexican population harbors novel and unique genetic variation underlying memory decline. Future work will include a larger sample (approximately 10,000 participants) and trans‐ethnic meta‐analysis with additional Caribbean‐Hispanics, African‐Americans and non‐Hispanic Whites cohorts.