MedGen

The DSM-IV (American Psychiatric Association, 1994) defines panic disorder as the spontaneous, unexpected occurrence of panic attacks followed by persistent concern, worry, and anxiety about having additional panic attacks. Panic attacks are defined as a discrete period of intense fear or discomfort in which at least 4 of 13 symptom criteria are met that develop abruptly and reach a peak within 10 minutes. Some of these criteria include cardiac palpitations, sweating, feelings of choking, fear of losing control, and fear of dying. Panic disorder is divided into panic disorder with or without accompanying agoraphobia. However, agoraphobia can also occur without panic disorder, and panic attacks can occur in the absence of panic disorder. Comorbidity with depressive and addictive disorders is frequent. Barlow et al. (1994) and Smoller and Tsuang (1998) noted that because the diagnostic criteria remain purely clinical, the nosology of anxiety disorders, such as panic disorder, is controversial and evolving. Therefore, it is difficult to do genetic studies because of the difficulty in delineating overlapping phenotypes within the broader context of anxiety disorders. For example, there may be overlap of panic with specific phobias, variable expressivity of panic and anxiety or depression, or phenocopies within a family. The terms 'anxiety neurosis' and 'phobic neurosis' were used in the past (before the DSM-III in 1980) to encompass all of these disorders. Smoller and Tsuang (1998) suggested that dimensional personality traits, such as shyness, behavioral inhibition, and neuroticism (see 607834), could be used to define an anxiety phenotype. Schumacher et al. (2011) provided a review of the genetics of panic disorder. They noted that there is high (80%) comorbidity with other psychiatric disorders, including agoraphobia, mood disorders, substance abuse, and other anxiety disorders. Associated personality traits include anxiety sensitivity, behavioral inhibition, neuroticism, and harm avoidance. Women are more susceptible to development of the disorder, which has an average age of onset at 23.6 years. Genetic Heterogeneity of Susceptibility to Panic Disorder Susceptibility to panic disorder-1 (PAND1) has been mapped to chromosome 13q. See also PAND2 (607853), mapped to chromosome 9, and PAND3 (609985), mapped to chromosome 4. [from OMIM]

Schizophrenia is highly heritable, as shown by family, twin, and adoption studies. For example, for identical twins, if one twin develops schizophrenia, the other twin has about a 50% chance of also developing the disease. The risk of the general population developing the schizophrenia is about 0.3-0.7% worldwide. The search for “schizophrenia genes” has been elusive. Initial linkage studies looked at parts of the genome associated with schizophrenia, and many candidate genes were identified, including APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53, and TPH1. However, some of these have later been questioned. Microdeletions and microduplications have been found to be three times more common in individuals with schizophrenia, compared to controls. Because these deletions and duplications are in genes that are overexpressed in pathways related to brain development, it is possible that the inheritance of multiple rare variants may contribute to the development of schizophrenia. Several genetic disorders feature schizophrenia as a clinical feature. The 22q11.2 Deletion Syndrome comprises many different syndromes, of which one of the most serious is DiGeorge syndrome. Children born with DiGeorge syndrome typically have heart defects, cleft palate, learning difficulties, and immune deficiency. Schizophrenia is a late manifestation, affecting around 30% of individuals. Microdeletions and duplications in chromosome 1, 2, 3, 7, 15 and 16 have also been associated with schizophrenia. In 2014, a genome-wide association study looked at the genomes of over 35,000 patients and 110,00 controls. The study identified 108 SNPs that were associated with schizophrenia, 83 of which had not been previously reported. As expected, many of these loci occurred in genes that are expressed in the brain. For example, the SNPs included a gene that encodes the dopamine D2 receptor, DRD2 (the target of antipsychotic drugs), and many genes involved in glutamine neurotransmitter pathways and synaptic plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1). More surprisingly, however, associations were also enriched among genes expressed in tissues with important immune functions. In 2016, a study based on nearly 65,000 people investigated the association between schizophrenia and variation in the Major Histocompatibility Complex (MHC) locus—a region on chromosome 6 that is important for immune function. The study focused on the C4 gene (complement component 4) that exists as two distinct genes: C4A and C4B, which encode particularly structurally diverse alleles. The study found that the alleles which promoted greater expression of C4A in the brain were associated with a greater risk of schizophrenia. By using mice models, the study showed that C4 is involved in the elimination of synapses during brain maturation. In humans, “synaptic pruning” is most active during late adolescence, which coincides with the typical onset of symptoms of schizophrenia. It is therefore possible that the inheritance of specific C4A alleles could lead to “run away” synaptic pruning, increasing the risk of schizophrenia. Further research may even determine C4 as a potential therapeutic target. [from Medical Genetics Summaries]