Bipolar disorder is a common, complex genetic disorder, but the mode of transmission remains to be discovered. Many researchers assume that common genomic variants carry some risk for manifesting the disease. The research community has celebrated the first genome-wide significant associations between common single nucleotide polymorphisms (SNPs) and bipolar disorder. Currently, attempts are under way to translate these findings into clinical practice, genetic counseling, and predictive testing. However, some experts remain cautious. After all, common variants explain only a very small percentage of the genetic risk, and functional consequences of the discovered SNPs are inconclusive. Furthermore, the associated SNPs are not disease specific, and the majority of individuals with a “risk” allele are healthy. On the other hand, population-based genome-wide studies in psychiatric disorders have rediscovered rare structural variants and mutations in genes, which were previously known to cause genetic syndromes and monogenic Mendelian disorders. In many Mendelian syndromes, psychiatric symptoms are prevalent. Although these conditions do not fit the classic description of any specific psychiatric disorder, they often show nonspecific psychiatric symptoms that cross diagnostic boundaries, including intellectual disability, behavioral abnormalities, mood disorders, anxiety disorders, attention deficit, impulse control deficit, and psychosis. Although testing for chromosomal disorders and monogenic Mendelian disorders is well established, testing for common variants is still controversial. The standard concept of genetic testing includes at least three broad criteria that need to be fulfilled before new genetic tests should be introduced: analytical validity, clinical validity, and clinical utility. These criteria are currently not fulfilled for common genomic variants in psychiatric disorders. Further work is clearly needed before genetic testing for common variants in psychiatric disorders should be established.

Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

ObjectivesThyroid abnormalities in patients with bipolar disorder (BD) have been linked to lithium treatment for decades, yet other drugs have been less well studied. Our objective was to compare hypothyroidism risk for lithium versus the anticonvulsants and second‐generation antipsychotics commonly prescribed for BD.MethodsAdministrative claims data on 24,574 patients with BD were analyzed with competing risk survival analysis. Inclusion criteria were (i) one year of no prior hypothyroid diagnosis nor BD drug treatment, (ii) followed by at least one thyroid test during BD monotherapy on lithium carbonate, mood‐stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, or carbamazepine) or antipsychotics (aripiprazole, olanzapine, risperidone, or quetiapine). The outcome was cumulative incidence of hypothyroidism per drug, in the presence of the competing risk of ending monotherapy, adjusted for age, sex, physician visits, and thyroid tests.ResultsAdjusting for covariates, the four‐year cumulative risk of hypothyroidism for lithium (8.8%) was 1.39‐fold that of the lowest risk therapy, oxcarbazepine (6.3%). Lithium was non‐statistically significantly different from quetiapine. While lithium conferred a higher risk when compared to all other treatments combined as a group, hypothyroidism risk error bars overlapped for all drugs. Treatment (p = 3.86e‐3), age (p = 6.91e‐10), sex (p = 3.93e‐7), and thyroid testing (p = 2.79e‐87) affected risk. Patients taking lithium were tested for hypothyroidism 2.26–3.05 times more frequently than those on other treatments.ConclusionsThyroid abnormalities occur frequently in patients with BD regardless of treatment. Therefore, patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood.

BackgroundBipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.MethodologyIn the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.ResultsBipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10−8). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10−8) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10−8) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.ConclusionConceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.

Cervical teratomas are rare tumours which are the result of abnormal prenatal development. They are usually detected at birth, but can occasionally remain silent until adulthood. Obstruction of the airway is the major challenge in the neonatal period. Prenatal diagnosis allows for early consultation with paediatric surgical specialists, so that the time and place of delivery can be addressed, and planning for resuscitative efforts can be organized in advance. If the airway is quickly stabilized and resection of the tumour is not delayed, the prognosis is good. Cervical teratomas in neonates are usually benign; however, malignant transformation and metastasis can occur as a rare event, influencing long‐term survival and prognosis. We present two cases of neonatal cervical teratoma detected prenatally by ultrasound. In one case, termination of the pregnancy was elected. In the other case, the child was delivered at 36 weeks' gestation, an airway was secured, and subtotal resection of the tumour was performed. No developmental or neurological deficit has been detected on long‐term follow‐up at 5 years of age. We present a review of the literature, with attention to outcome and potential for malignancy in neonatal cervical teratomas, in order to provide help in decision‐making, once prenatal diagnosis is made. © 1998 John Wiley & Sons, Ltd.