Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate.

Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

A 10-year prospective study of prodromal patterns for bipolar disorder among Amish youth.

OBJECTIVE: Prospective study of well children at risk of bipolarity to identify the frequency and pattern of potentially prodromal symptoms/behaviors for bipolar disorder type I (BPI) disorder. METHOD: A total of 110 at-risk children with a BPI parent and 112 children with well parents were studied. Ten-year data collection used structured and semistructured annual interviews covering developmental, medical, and behavioral features. Randomized histories for 222 children were submitted blindly for risk rating of bipolarity by a panel of clinicians. RESULTS: Children in the bipolar sample had an overall risk rating of 41% as compared with 16% for control children. Features noted more frequently among the at-risk group were anxious/worried, attention poor/distractable in school, easily excited, hyper alert, mood changes/labile, role impairment in school, somatic complaints, and stubborn/determined. Five additional manic-like behaviors became more evident among at-risk adolescents at the 10-year follow-up: high energy, decreased sleep, problems with thinking/concentration, and excessive and loud talking. CONCLUSIONS: The children of a parent with BPI manifested, episodically, mini clusters of potentially prodromal characteristics more frequently than the children of normal controls. None of these children met any of the sets of diagnostic criteria for prepubertal bipolar disorder.

Transcriptomic Analysis of Induced Pluripotent Stem Cells Derived from Patients with Bipolar Disorder from an Old Order Amish Pedigree.

Fibroblasts from patients with Type I bipolar disorder (BPD) and their unaffected siblings were obtained from an Old Order Amish pedigree with a high incidence of BPD and reprogrammed to induced pluripotent stem cells (iPSCs). Established iPSCs were subsequently differentiated into neuroprogenitors (NPs) and then to neurons. Transcriptomic microarray analysis was conducted on RNA samples from iPSCs, NPs and neurons matured in culture for either 2 weeks (termed early neurons, E) or 4 weeks (termed late neurons, L). Global RNA profiling indicated that BPD and control iPSCs differentiated into NPs and neurons at a similar rate, enabling studies of differentially expressed genes in neurons from controls and BPD cases. Significant disease-associated differences in gene expression were observed only in L neurons. Specifically, 328 genes were differentially expressed between BPD and control L neurons including GAD1, glutamate decarboxylase 1 (2.5 fold) and SCN4B, the voltage gated type IV sodium channel beta subunit (-14.6 fold). Quantitative RT-PCR confirmed the up-regulation of GAD1 in BPD compared to control L neurons. Gene Ontology, GeneGo and Ingenuity Pathway Analysis of differentially regulated genes in L neurons suggest that alterations in RNA biosynthesis and metabolism, protein trafficking as well as receptor signaling pathways may play an important role in the pathophysiology of BPD.

Prospective study of prodromal features for bipolarity in well Amish children.

OBJECTIVE: A prospective study of psychiatrically well Amish children to determine differences in the frequency and pattern of clinical features that may be prodromal for bipolar I disorder. METHOD: Children with a bipolar I parent (n = 100) and children of well parents in a matched control sample (n = 110) were assessed annually for 7 years with semistructured interviews covering medical/developmental features and symptoms/behaviors that are possibly prodromal for bipolarity. Randomized histories of these 210 children were evaluated blindly by 4 clinicians for independent ratings of risk for bipolarity. RESULTS: Thirty-eight percent of the children of bipolar parents were rated as at risk compared with 17% of children in the control sample. Most control sample children with risk ratings had well parents with a bipolar sibling (i.e., family history positive). Children with family histories negative for mental illness rarely received even a low risk rating. Clinical features significantly (p

A 16-year prospective study of prodromal features prior to BPI onset in well Amish children.

BACKGROUND: Longitudinal research of well Amish children over 16 years to identify the pattern and frequency of prodromal symptoms/behaviors associated with onset of BPI disorder during childhood or adolescence. METHODS: Parental informants were interviewed annually using structured and semi-structured interviews to record medical, developmental and behavioral/symptomatic data for their children in two samples. The bipolar sample had 115 children with a BPI parent. The control sample had 106 children of well parents, with and without a positive family history for mood disorders. A panel of clinicians assigned risk ratings independently and blind to family relations. RESULTS: Eight children, age 13 or older, onset with BPI in the bipolar sample compared with one in the control sub-sample (well parent of a BPI sibling). The specific "pre-school" behaviors/symptoms that most identified children with BPI from well children in control samples were: sensitivity, crying, hyper-alertness, anxiety/worry and somatic complaints. During school years, parents reported mood (sad) and energy changes (low not high) decreased sleep and fearfulness as key symptoms. LIMITATIONS: The sample of 9 BPI onsets is small. However, a variable age of onset means many children remain at risk. Although not statistically significant, 34.6% of the bipolar sample youngsters carry risk ratings compared to 15.2% among controls. CONCLUSIONS: The miniclusters of prodromal features that emerged pre-school (ages 1-6), were "episodic" through childhood (7-12) and appeared to mimic adult recurrent illness. Prepubertal onset with mania did not occur. The pattern of prodromal symptoms has clinical relevance for its potential predictive value for onset with BPI disorder and early intervention.