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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes.
Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns.
Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups.
With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.
The inconsistency in linkage results that has bedeviled psychiatric genetics has been observed to occur regularly in common diseases with complex inheritance. Nonetheless, in two such instances—noninsulin-dependent diabetes mellitus (NIDDM) and inflammatory bowel disease (IBD)—susceptibility genes have been discovered based on the follow-ups of linkage findings. In bipolar illness disorder (BPD) and schizophrenia (SZ), there are some linkage reports with replication of other studies similar to the situation in NIDDM and IBD before the successful positional cloning efforts. Two of the regions with linkage reports, BPD and SZ, on the long arms of chromosomes 13 and 22, show linkage to the same markers in both diseases. This lends some plausibility to the hypothesis of some shared genetic predispositions for both disorders. Cytogenetic evidence offers another positional approach to susceptibility genes. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BPD and SZ. Endophenotypes ofSZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to 6p, and an abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to the psychiatric illnesses. These genetic findings may contribute to etiologic subcategorization of BPD and SZ, and the development of new treatment approaches. A table of genetic terms is included for review.
Many studies have estimated heritability of body mass index (BMI) and related variables, and they are consistent in finding moderate to high heritability. Genes central to energy balance tend to have low variability, presumably because of strong selection pressure. Even so, some have argued that mutations in a large number of genes may account for most human obesity and other common diseases. Substantial progress in finding rare variants has come with a focus on copy number variation (CNV). Whole genome association (WGA) studies have several advantages over whole genome linkage scans. Gene-environment interaction can play an important role in the development of obesity, although it should be born in mind that this may only complicate things further, as environmental response is itself heritable. Epigenetics are discussed in this chapter. WGA studies results have demonstrated that there are indeed common variants in genes that increase risk for obesity.
Serum antibody titres to herpes-simplex (HSV-1, 2), cytomegalovirus (CMV), and Epstein–Barr virus capsid antigen (EBV-VCA) were determined in 38 unrelated chronic schizophrenic patients, 11 nuclear families with at least 2 schizophrenic members, and 2 control groups. The distributions of antibody titres to herpes simplex and cytomegalovirus were similar among all groups. Patients had higher anti-EBV-VCA titres than non-hospitalized controls; however, hospital staff members in contact with the patients also had significantly higher antibody titres to EBV-VCA. Antibodies to EBV early antigen (EBV-EA) were also determined for 27 unrelated patients and 24 mental hospital employees. The schizophrenic patients had significantly higher antibody titres to EBV-EA than the hospital worker control group. These data do not support the hypothesis that herpes viruses are associated with the aetiology of schizophrenia. Although elevated anti-EBV early antigen titres may suggest persistent active EBV infection, it is unlikely to be related to the aetiology of the disorder, since discordance for EBV seropositivity was present among sibling pairs concordant for schizophrenia.
All the children (ages 5–15) of 14 consecutive patients admitted to hospital at the National Institute of Mental Health with a diagnosis of bipolar or unipolar affective disorder were studied. The children were seen twice, four months apart, and assessed by an interview and rating scales. The parents were also assessed. Of 14 boys, five were depressed on both interviews and three were depressed on one interview. Four of the 16 girls were depressed on both interviews and 11 were depressed on one interview. The clinical picture and the ratings showed the boys, but not the girls, to have a significant correlation for depression on both interviews. The children diagnosed as suffering from depression showed the symptoms of a primary unipolar affective disorder without other significant pathology.
An analysis of recently published family history data on rapid eye movement (REM) narcolepsy was undertaken to determine the goodness-of-fit of a multifactorial (MF) model of inheritance. The analysis revealed that a two-threshold MF model can successfully account for the prevalence of REM narcolepsy and other disorders of excessive sleep (DES) observed in the first-degree relatives of the REM narcoleptic probands studied.
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