Advanced paternal age at birth: phenotypic and etiologic associations with eating pathology in offspring.

Advanced paternal age at birth is a risk factor for psychiatric disorders in offspring, including schizophrenia, autism, and bipolar disorder (Malaspina et al., 2001, Reichenberg et al., 2006, Frans et al., 2008). These relationships have been confirmed in meta-analytic studies (Wohl and Gorwood, 2007, Hultman et al., 2011, Miller et al., 2011) and are independent of important confounds (i.e., maternal age at birth, socioeconomic status (SES), parental psychiatric history) that increase psychiatric risk and are associated with later entry into parenthood (Byrne et al., 2003, Croen et al., 2007, Menezes et al., 2010). Recent data also link paternal age to obesity (Eriksen et al., 2012). Despite these robust effects, advanced paternal age has never been examined as a risk factor for eating disorders in offspring. Examining this possibility could provide new insights into the complex etiology of eating disorders. Leading theories propose that de novo genetic mutations are primary mechanisms underlying paternal age-psychiatric risk associations (Malaspina et al., 2002). The increased probability of DNA copy error problems with each sperm replication (~610 replications by age 40), and the accumulation of mutations in the germline of older fathers, are thought to lead to disease phenotypes in offspring (Crow, 2000). Genetic studies indicate that offspring de novo mutation rates are influenced by paternal age at conception (Kong et al., 2012), and de novo mutations are implicated in schizophrenia and autism (Awadalla et al., 2010, Xu et al., 2011, Iossifov et al., 2012). However, to our knowledge, no study has directly confirmed that de novo mutations underlie paternal age-offspring psychiatric risk associations. Twin studies can be used to indirectly examine the role of de novo mutations in paternal age-psychiatric disorder relationships. Because monozygotic (MZ) twins share 100% of their genes, and dizygotic (DZ) twins share, on average, half of their segregating genetic material, MZ twins would be expected to share all de novo mutations, whereas DZ twins would almost never share genetic mutations given their rarity (Zhao et al., 2007, Liu et al., 2010, Ronald and Hoekstra, 2011). If de novo mutations underlie paternal age–psychiatric risk associations, larger differences between MZ and DZ twin correlations should be observed with advancing paternal age since DZ co-twins should become less similar as mutation rates increase. One previous study examined these processes by investigating twin similarity for autism across paternal age (Lundstrom et al., 2010). Importantly, differences in MZ/DZ concordance for autism decreased with advanced paternal age, implicating environmental rather than genetic processes. Although results were limited by a small number of cases in each age category (Ns = 3–44), they highlight the need to test hypotheses regarding mechanisms for paternal age effects. Twin registries are excellent, low-cost resources for such investigations, as they can indirectly examine whether de novo mutations or other competing processes most likely underlie paternal age-psychiatric risk associations. The current study investigated phenotypic and etiologic associations between advanced paternal age and disordered eating symptoms (e.g., weight/shape concerns) in a large, population-based sample of female twins. These symptoms are core features of eating disorders and prospectively predict the development of diagnoses (Jacobi et al., 2004); thus, results should inform risk models of eating disorders. Exploratory analyses examining associations between advanced paternal age and an eating disorder history (anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED)) were also conducted to investigate whether results generalize across categorical and continuous eating disorder dimensions (American Psychiatric Association, 2000; Insel et al., 2010). Several covariates were included (e.g., maternal age, body mass index (BMI) percentile, SES, fertility treatment, parental psychiatric history) to ensure that associations were not due to confounding factors. Finally, we compared twin similarity for disordered eating across paternal age to explore mechanisms (i.e., genetic/environmental) underlying paternal age-disordered eating associations.