• Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia

      Wang, Shi-Heng; Hsiao, Po-Chang; Yeh, Ling-Ling; Liu, Chih-Min; Liu, Chen-Chung; Hwang, Tzung-Jeng; Hsieh, Ming H.; Chien, Yi-Ling; Lin, Yi-Ting; Huang, Yen-Tsung; et al. (Elsevier BV, 2019-07)
      BACKGROUND:Whether paternal age effect on schizophrenia is a causation or just an association due to con-founding by selection into late parenthood is still debated. We investigated the association between paternal age andearly onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia asempirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium.METHODS:Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research inTaiwan project, 1649 had parents’genotyping data. The relationships of paternal schizophrenia PRS to paternal ageatfirst birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model ofpatients’early onset of schizophrenia (#18 years old) on paternal age was conducted.RESULTS:Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset ofschizophrenia (odds ratio per 10-year increase in paternal age = 1.28,p= .007) after adjusting for maternal age, sex,and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, aU-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting forboth paternal and maternal schizophrenia PRS, the association of paternal age with patients’early onset ofschizophrenia remained (odds ratio = 1.29,p= .04).CONCLUSIONS:The association between paternal age and early onset of schizophrenia was not confounded byparental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Ourfindingssupport an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring
    • Meta-Analysis of Alzheimer's Disease Risk with Obesity, Diabetes, and Related Disorders

      Profenno, Louis A.; Porsteinsson, Anton P.; Faraone, Stephen V. (Elsevier BV, 2010-03)
      Background: Late-onset Alzheimer’s disease (AD) is a multifactorial and heterogeneous disorder with major risk factors including advanced age, presence of an apolipoprotein E 4 (APOE4) allele, and family history of AD. Other risk factors may be obesity and diabetes and related disorders, which are highly prevalent. Methods: We reviewed longitudinal epidemiological studies of body mass, diabetes, metabolic syndrome, and glucose and insulin levels on risk for AD. We conducted meta-analyses of the results from these studies. Results: For obesity assessed by body mass index, the pooled effect size for AD was 1.59 (95% confidence interval [CI] 1.02–2.5; z 2.0; p .042), and for diabetes, the pooled effect size for AD was 1.54 (95% CI 1.33–1.79; z 5.7; p .001). Egger’s test did not find significant evidence for publication bias in the meta-analysis for obesity (t 1.4, p .21) or for diabetes (t .86, p .42). Since these disorders are highly comorbid, we conducted a meta-analysis combining all studies of obesity, diabetes, and abnormal glucose or insulin levels, which yielded a highly significant pooled effect size for AD of 1.63 (95% CI 1.39 –1.92; z 5.9; p .001). Conclusions: Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
      Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged not only by case reports, but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: 1) its pattern of comorbidity may be unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder, aggression, and conduct disorder; 2) its overlap with substance use disorders; 3) its association with trauma and adversity; and 4) its response to treatment is atypical by adult standards. Biol Psychiatry 2000;48: 458–466 © 2000 Society of Biological Psychiatry.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
    • RASD2, MYH9, and CACNG2 Genes at Chromosome 22q12 Associated with the Subgroup of Schizophrenia with Non-Deficit in Sustained Attention and Executive Function

      Liu, Yu-Li; Fann, Cathy Shen-Jang; Liu, Chih-Min; Chen, Wei J.; Wu, Jer-Yuarn; Hung, Shuen-Iu; Chen, Chun-Houh; Jou, Yuh-Shan; Liu, Shi-Kai; Hwang, Tzung-Jeng; et al. (Elsevier BV, 2008-11)
      Background: In a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p .001). Methods: We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 Mb of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST). Results: Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p .0163 with haplotype analysis). Conclusions: The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.
    • Shared polygenic risk for ADHD, executive dysfunction and other psychiatric disorders

      Chang, Suhua; Yang, Li; Wang, Yufeng; Faraone, Stephen V. (Springer Science and Business Media LLC, 2020-06-09)
      Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n = 1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P = 0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P = 0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P = 0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.