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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.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
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.
Results
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.
Conclusions
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.
Schizophrenia patients and their relatives have
saccadic abnormalities characterized by problems inhibiting
a response. The dorsolateral prefrontal cortex and its
associated circuitry ostensibly mediate inhibition and
support correct delayed response performance. In this context,
two components of delayed response task performance are
of interest: memory saccade metrics and error saccades
made during the delay. To evaluate these variables, an
ocular motor delayed response task was presented to 23
schizophrenia patients, 25 of their first-degree biological
relatives, and 19 normal subjects. The measure that best
differentiated groups was an increased frequency of error
saccades generated during the delay by schizophrenia subjects
and relatives. Decreased memory saccade gain also characterized
patients and relatives. The similar pattern of results
demonstrated by the patients with schizophrenia and their
relatives suggests that performance on ocular motor delayed
response tasks, either alone or in combination with other
saccadic variables, may provide useful information about
neural substrates associated with a liability for developing
schizophrenia.
The ability to identify unaffected gene carriers
within families may be crucial to the success of schizophrenia
genetics studies. Data collected from three family samples
(N = 365) demonstrated that poor antisaccade performance
is an exceptionally promising indicator of liability for
schizophrenia. A particular antisaccade task version provides
large separations (5–6 sigma) between proband and
normal groups. Poor antisaccade performance alone correctly
identified 70% of patients in California, Utah, and Micronesia
schizophrenia samples. Twenty-five to 50% of these patients'
nonpsychotic first-degree relatives also had poor antisaccade
performance, yielding risk ratios around 20:1 for simplex
and 50:1 for multiplex schizophrenia families. Poor antisaccade
performance is associated with dorsolateral prefrontal
cortex pathology, suggesting that dysfunction of this circuitry
also may predispose individuals to developing this disease.
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