In this study, a recent large-scale GWAS data was utilized to obtain 814 loci associated with dietary habits. The UK Biobank data were used to conduct PRS analysis for each individual of depression and intelligence, respectively. The GWEI analyses were performed to detect significant SNP × dietary habit interaction effects on depression and intelligence, respectively. Our study observed associations of dietary habit with depression and intelligence, and detected several candidate loci that interacted with dietary habits for depression and intelligence.
Multiple common dietary habits associated with depression and intelligence were observed in this study, such as overall alcohol intake and red wine glasses per month. Alcohol consumption has highly negative effects that contribute to the symptoms in many neuropsychiatric disorders . Churchill et al. suggested that alcohol consumption might induce depression, and consistently related to several measures of drinking behavior, including alcohol consumption intensity, alcohol dependence and risk of dependence . Interestingly, evidence about the relationship between intelligence and alcohol intake were complicated, with researchers reported evidence of a positive relationship  and a negative relationship . Laust et al. assessed the association between intelligence and preferred beverage type in young Danish men, and found that high intelligence was associated with the preference for wine . While the considerable associations of alcohol intake with depression and intelligence were reported, the causal relationships and biological mechanisms remain elusive now.
Never eat sugar vs. no sugar restrictions was detected to be associated with depression. Higher sugar consumption was linked to higher depression prevalence in several ecological and cross-sectional studies [41, 42]. Likewise, a western diet riches in sugar and fat might increase the risk of depression . A recent meta-analysis also indicated that the consumption of sugar-sweetened beverages might associate with a modestly higher risk of depression . Knüppel et al. performed a random effects regression to repeated measures, and suggested that high long-term consumption of carbohydrates has adverse effects on psychological health, even leaded to higher rate of depression . In six countries, a highly significant correlation was detected between sugar consumption and the annual rate of depression . The above studies strongly support our result that sugar consumption may closely relate to the risk of depression.
Interaction analysis of depression indicated that OLFM1 (olfactomedin 1) had interaction effects with champagne/white wine glasses per month. OLFM1 is a glycoprotein highly expressed in human brain, and may have an essential role in nerve tissue . Nakaya et al. confirmed that OLFM1 participated in neural progenitor maintenance and cell death in brain . OLFM1 was also demonstrated to be related to amyotrophic lateral sclerosis due to its regulation of motor cortex and spinal cord . Our result suggests that OLFM1 gene expression may be involved in the mechanism between champagne/white wine and depression. Additionally, several suggestively significant SNP-dietary interactions were observed in depression GWEI, such as interaction between rs117916244 (PTPRJ) and total drinks of alcohol per month, and interaction between rs62169868 (KYNU) and red wine glasses per month. The regulation of the ephrin-Eph-c-Abl axis by PTPRJ plays a vital role in the proper central projection of retinal axons during development . Wigner et al. confirmed that venlafaxine modulated the expression and methylation level of KYNU in brain when rats exposed to the chronic mild stress model of depression . The SNP-dietary interactions suggest that PTPRJ and KYNU may play a role in alcohol-induced depression.
Caffeine was detected for intelligence in this study. The cognitive enhancing properties of caffeine were facilitated by its indirect effects on mood and attention . A memory and intelligence test supported that intelligence was declined by small dose of caffeine, while associative reproduction of idea was improved by caffeine . Corley et al. collected intelligence quotient data from 923 healthy participants at age 11 and assessed their cognitive function at age 70, and found that higher cognitive scores were associated with caffeine consumption . Likewise, Rees et al. assessed the influence of age on the effects of caffeine on a variety of psychomotor and cognitive tests, and observed that the psychomotor performance and cognitive function in participants were improved after caffeine consumption . A recent systematic review highlighted the benefit of caffeine on memory, crystallized intelligence, physical and occupational performance . In genetic perspective, our research may suggest an effect of caffeine intake on intelligence.
Our interaction analysis of intelligence highlighted SYNPO2 (synaptopodin-2) was a significant gene interacted with dietary habit-coffee type: decaffeinated vs. any other. SYNPO2 is mainly expressed in human brain tissue and has been demonstrated to associate with several mental disorders . For example, Zhang et al. observed that SYNPO2 was one of the differentially expressed genes in schizophrenia . The GWASdb SNP-Phenotype association dataset showed that SYNPO2 was associated with the schizophrenia phenotype in GWAS datasets . SYNPO2 was demonstrated to closely associate with cognitive development in mice brain . Chronic variable stress in mice induced significantly down-regulation of SYNPO2 which was necessary for synaptic plasticity, learning and memory . Although there is less evidence to link caffeine consumption to SYNPO2 expression change, our result suggests that caffeine may influence the intelligence by affecting the expression of SYNPO2 in human brain.
Notably, there are also two limitations in this study. Although the dietary habits and GWEI reported in this study are significantly related to depression and intelligence, and consistent with some previous evidences, further experimental studies are needed to explore and confirm the underlying molecular biological mechanisms. In addition, the GWAS and dietary habits data in this study were obtained from European ancestry, which should be careful to apply on other race.