The main aim of this study was to investigate serum levels of adiponectin in adult patients with attention deficit hyperactivity disorder (ADHD). The second objective was to examine the effects of rare missense mutations in T-cadherin, an adiponectin receptor encoded by the ADHD candidate gene CDH13, on serum adiponectin levels. Total and high molecular weight (HMW) adiponectin levels were measured by an enzyme-linked immunosorbent assay in 44 patients and 29 controls. We found decreased serum adiponectin levels in ADHD patients. In a logistic regression model, adjusting for confounding by age, body mass index, and gender, HMW adiponectin and its ratio to total adiponectin were significantly associated with ADHD. In partial correlations, HMW adiponectin and its ratio to total adiponectin were significantly inversely correlated with self-reported psychiatric symptomatology. A non significant trend for higher levels of total adiponectin was observed in patients carrying CDH13 missense mutations compared to patients with wild type CDH13. The association of CDH13 mutations with adiponectin levels should be investigated in larger studies. This study shows that ADHD patients have decreased serum adiponectin levels, which are inversely correlated to psychiatric symptoms, suggesting a possible involvement of adiponectin, in particular the HMW form, in the pathophysiology of ADHD.
Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder with worldwide prevalence estimates of around 5–10% (Faraone et al., 2003 and Polanczyk et al., 2007). ADHD often persists into adulthood with a prevalence of around 3–5% in young adults (Fayyad et al., 2007 and Simon et al., 2009). Although around 75% of the variability in childhood ADHD symptomatology is accounted for by genetic factors (Faraone and Doyle, 2001), unequivocal genetic associations with ADHD have not been identified yet (Faraone et al., 2005 and Franke et al., 2012). Research in ADHD etiology has revealed several biological and psychosocial risk factors for this disorder, such as maternal smoking (Langley et al., 2005) and alcohol consumption during pregnancy (Banerjee et al., 2007), pre-term birth and low birth weight (Halmoy et al., 2012), maternal stress, environmental toxin exposure, and childhood adversity (Biederman, 2005). Still, the biological mechanisms mediating these risk factors have not yet been identified and few biomarkers have shown consistent associations with ADHD (Scassellati et al., 2012).
An increased prevalence of obesity, cardiovascular disease and diabetes mellitus has been reported in disorders like major depression, bipolar disorder, and schizophrenia (Bai et al., 2013, Stanley and Laugharne, 2012 and Stanley et al., 2013). Likewise, recent studies have shown co-occurrence of obesity and ADHD in children (Agranat-Meged et al., 2005 and Halfon et al., 2013) and adults (Fleming et al., 2005). Moreover, there is evidence that obesity genes such as the FTO gene, which codes for the enzyme alpha-ketoglutarate-dependent dioxygenase, may affect ADHD risk ( Choudhry et al., 2013) and that obesity and ADHD may share common risk alleles ( Albayrak et al., 2013). Thus, these co-morbidities may reflect a common etiology or the involvement of common pathways, as well as a cross-talk between adipose tissue and the central nervous system ( Schulz et al., 2010).
In line with these findings, abnormal circulating levels of hormones secreted by adipose tissue, such as the adipocytokine adiponectin, have been detected in obesity (Arita et al., 1999 and Ryo et al., 2004), type II diabetes and insulin resistance (Kadowaki et al., 2006 and Yatagai et al., 2003), but also in patients with psychiatric disorders such as major depression (Leo et al., 2006), schizophrenia (Cohn et al., 2006), panic disorder (Unsal et al., 2012) and bipolar disorder (Barbosa et al., 2012). Adiponectin is an adipokine hormone that has insulin-sensitizing (Shehzad et al., 2012) and anti-inflammatory effects (Wolf et al., 2004), stimulates fatty acid oxidation (Yamauchi et al., 2001), and its expression is regulated by insulin (Scherer et al., 1995), testosterone (Nishizawa et al., 2002), and glucocorticoids (Sukumaran et al., 2012). Adiponectin molecules circulate in the blood mainly as trimers of 30 kDa subunits and multimers composed of combinations of trimers and hexamers (Kadowaki and Yamauchi, 2005 and Tsao et al., 2003). The diverse functions of adiponectin are mediated by the AdipoR1 and AdipoR2 receptors that show predominant expression in muscle and liver, respectively, (Yamauchi et al., 2003) but are also expressed in the brain (Thundyil et al., 2012). A third adiponectin receptor, T-cadherin, selectively binds the hexameric and high molecular weight forms (HMW) of adiponectin and is abundantly expressed in the cardiovascular system and the brain (Hug et al., 2004). Several genome wide association (GWA) studies have detected associations between single nucleotide polymorphisms (SNPs) in the region of the CDH13 gene, which codes for T-cadherin, and ADHD ( Lasky-Su et al., 2008 and Lesch et al., 2008). Moreover GWA studies have shown a strong association of CDH13 polymorphisms with serum levels of adiponectin ( Morisaki et al., 2012 and Wu et al., 2010). Based on these findings, we wanted to examine serum adiponectin levels in ADHD and the effects of missense mutations in CDH13 on serum adiponectin levels.
The main aim of this study was to compare serum adiponectin levels, and adiponectin multimer distribution, in a sample of ADHD patients and population derived controls. The second aim was to investigate the effects of missense heterozygous CDH13 mutations, previously identified in our sample ( Mavroconstanti et al., 2013) on the serum levels of adiponectin by comparing two subgroups of adult ADHD patients: (1) carriers of wild type CDH13 and (2) carriers of either one of seven rare CDH13 mutations.
