Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males

Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation

“…Table 2 shows that we did not replicate any of the associations between loneliness and specific candidate genes that had been previously reported. None of these SNPs showed significant evidence for association (p ⩽ 0.05 without correction for multiple comparisons), with the exception of the gene MTHFR (Table 2), for which the direction of the association in our data was opposite to what was reported previously (Lan et al, 2012). Therefore, none of the previously reported associations could be replicated, despite our large sample size.…”

“…We did not identify any genome-wide significant associations (Figure 1 and Supplementary Figures S4-S6), presumably reflecting the very modest contributions of individual variants. Previous studies have reported associations between polymorphisms in a handful of candidate genes and loneliness (Chou, 2010;Chou et al, 2014;Connelly et al, 2014;Lan et al, 2012;Lucht et al, 2009;Terracciano et al, 2010;Tsai et al, 2012;van Roekel et al, 2010van Roekel et al, , 2011van Roekel et al, , 2013Verhagen et al, 2014;Wang et al, 2013); our study did not provide even nominal evidence for replication, despite our much larger sample size (Table 2). Finally, we identified varying levels of evidence for coheritability between personality traits (positive for neuroticism and negative for extraversion) and psychiatric disease traits (negative for schizophrenia and bipolar disorder and positive for depression).…”

“…Therefore, although our study benefited from a larger sample size than any of the previously reported candidate gene studies, we cannot discount the possibility that differences in the methodologies or the population under study led to our failure to replicate the previously published results. The phenotyping procedure used in the current study has been found to correlate highly (r = 0.88) with a more in-depth phenotype for loneliness (Hughes et al, 2004), and the candidate gene studies using older adults from the United Kingdom and Taiwan provided no greater evidence for replication than the studies using adolescents (Chou, 2010(Chou, , 2014Connelly et al, 2014;Lan et al, 2012;Tsai et al, 2012;Wang et al, 2013).…”

“…We identified 13 variants in 11 genes that have previously been associated with loneliness phenotypes in the published literature (Chou, 2010(Chou, , 2014Connelly et al, 2014;Lan et al, 2012;Lucht et al, 2009;Terracciano et al, 2010;Tsai et al, 2012;van Roekel et al, 2010van Roekel et al, , 2011van Roekel et al, , 2013Verhagen et al, 2014;Wang et al, 2013). We examined the association of each of these SNPs with loneliness (linear, multivariate, and case/ control) in the results from the GWAS described above.…”

MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder

“…Nonetheless, C677T and A1298C SNPs have been strongly associated with decreased MTHFR activity (Frosst et al, 1995; der Put et al, 1998;Ulvik et al, 2007), controversial results have been found regarding their role in the genetic vulnerability to depression and in the final effects on blood folate levels (Moorthy et al, 2012;Wu et al, 2013;Zappacosta et al, 2014;Gatt et al, 2015). Regarding MTHFR C677T, several studies have shown an increased risk for MDD in T allele or TT genotype individuals (Arinami et al, 1997;Bjelland et al, 2003;Lewis et al, 2006;Shen et al, 2014), but numerous studies have not found significant associations (Kunugi et al, 1998;Hickie et al, 2001;Tan et al, 2004;Reif et al, 2005;Almeida et al, 2008;Gaysina et al, 2008;Hong et al, 2009;Lizer et al, 2011;Evinova et al, 2012;Lan et al, 2012;Lok et al, 2014). One study (Bousman et al, 2014) reported that bearing the 677CC genotype could increase an individual's probability of remaining depressed in the long term.…”