Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Is prematurity associated with adult cognitive outcome and brain structure?

Previous studies have indicated that preterm birth and low birth weight are associated with structural brain abnormalities and neurocognitive deficits in childhood and adolescence, although very few studies have included follow-up in adulthood. Here we assessed the effect of preterm delivery (524 subjects; mean 34.6 weeks, S.D. = 1.7) or low birth weight (366 subjects; mean 2159 g, S.D. = 303) on educational and occupational outcomes at age 31 years in the Northern Finland 1966 Birth Cohort, along with 10,132 term, normal birth weight control subjects. Cognitive tests and brain morphology using magnetic resonance imaging were assessed at age 33-35 years in a subset of the cohort (9 subjects; 95 controls). The preterm or low birth weight subjects had slightly lower school ratings and lower educational levels in adulthood, and they performed worse in verbal learning. The low birth weight subjects were less likely to be employed. There were no mean differences in the magnetic resonance imaging tissue segmentation analysis of the brain. In conclusion, although there were no overall changes in brain morphology in the preterm or low birth weight group, there was evidence for slightly poorer educational and occupational careers and cognitive capacity, which may reflect functional disruption not evident in structure.

The prevalence and predictive value of individual criteria for metabolic syndrome in schizophrenia: a Northern Finland 1966 Birth Cohort Study.

The metabolic syndrome (MetS) is associated with elevated risk of diabetes and cardiovascular morbidity. However, little is known of the sensitivity, specificity and predictive value of individual criteria in patients with schizophrenia. We studied the prevalence of MetS using the International Diabetes Federation (IDF) and adapted National Cholesterol Education Program (NCEP-ATPIII) criteria in the Northern Finland 1966 Birth Cohort population. In addition, the sensitivity, specificity and predictive values for individual criteria were determined. Both adapted NCEP-ATPIII and IDF criteria for MetS identified the same cases (29% of all schizophrenia patients). Among the IDF criteria, hypertriglyceridemia had the highest sensitivity, correctly identifying 77.8% of the patients. Reduced HDL cholesterol was the most specific criteria, with 95% specificity equalling a positive likelihood ratio of 9.78. Thus both the IDF and NCEP-ATPIII criteria may be equally useful in identifying MetS.

Morphometric brain abnormalities in schizophrenia in a population-based sample: relationship to duration of illness.

Biased recruitment and sample selection may cause variability in neuroimaging studies. Epidemiologically principled population-based magnetic resonance imaging (MRI) studies of schizophrenia are very rare. We gathered structural MRI data on 154 subjects from the Northern Finland 1966 Birth Cohort, aged 33-35 (100 controls, 54 schizophrenia patients). Regional differences in density of gray matter, white matter, and cerebrospinal fluid (CSF) were identified between groups using nonparametric statistical analysis, and the relationship of the regional differences to duration of illness was explored. Gray matter reductions were found bilaterally in the cerebellum, thalamus, basal ganglia, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, insula, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, cuneus, and lingual gyrus; in the left posterior cingulate, superior frontal gyrus, transverse temporal gyrus, and precuneus; and in the right postcentral gyrus. Gray matter excesses were observed bilaterally in the basal ganglia, anterior cingulate, and medial orbitofrontal cortices. There were white matter deficits in an extensive network including inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal, and occipital lobes, subcortical structures, cerebellum, and brain stem. CSF excesses were found bilaterally in the lateral ventricles, third ventricle, interhemispheric, and left Sylvian fissure. We replicated the previous findings of structural brain abnormalities in schizophrenia on a general population level. Gray and white matter deficits were associated with duration of illness suggesting either that developmental brain deficits relate to an earlier age of onset or that brain abnormalities in schizophrenia are progressive in nature.

Non-participation in a field survey with respect to psychiatric disorders.

AIMS: Higher rates of psychiatric morbidity among non-participants may lead to biased estimates of prevalence and incidence in epidemiological studies of psychiatric disorders. We had a unique opportunity to explore psychiatric morbidity and non-participation in a large epidemiological survey including questionnaires and a clinical examination. METHODS: Members of the Northern Finland 1966 Birth Cohort were included in the study. In phase I, a postal questionnaire was mailed to all those with a known address in 1997 (N=11,540). In phase II, all subjects living in northern Finland or the Helsinki area (N=8,463) were invited to a clinical examination. In phase III, clinical examination participants were given a questionnaire with psychological subscales to be filled in at home and returned by mail. The data on hospital-treated psychiatric disorders were obtained from the Finnish Hospital Discharge Register. Educational level was obtained from Statistics Finland. RESULTS: The participation rates were 76%, 71% and 61% in phases I, II and III, respectively. Subjects with any psychiatric disorder participated less actively than those without any psychiatric disorder in all phases, in both genders and at all educational levels. Participation was not found to vary across specific disorders. Gender or education did not explain the association of psychiatric disorders with participation. CONCLUSIONS: Owing to non-participation, the true prevalence of psychiatric disorders may be higher than the prevalence estimated from epidemiological field surveys.

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia.

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 Birth Cohort study.

OBJECTIVE: Schizophrenia is associated with a shortened life expectancy and increased somatic comorbidity with, e.g., cardiovascular disorders. One major risk factor for these disorders is the metabolic syndrome, which has been reported to have a higher frequency in schizophrenic patients. Our objective was to study the prevalence of metabolic syndrome in a population-based birth cohort. METHOD: The study sample consisted of 5613 members of the Northern Finland 1966 Birth Cohort who participated in the field study from 1997 to 1998. Subjects were divided into 4 diagnostic categories (DSM-III-R): (1) schizophrenia (N = 31), (2) other functional psychoses (N = 22), (3) nonpsychotic disorders (N = 105), and (4) no psychiatric hospital treatment (N = 5455, comparison group). Subjects were assessed for the presence of metabolic syndrome according to the criteria of the National Cholesterol Education Program. RESULTS: The prevalence of metabolic syndrome was higher in subjects with schizophrenia compared with the comparison group (19% vs. 6%, p = .010). The prevalence of metabolic syndrome in subjects with other psychoses was 5%. After controlling for sex, the results of logistic regression analysis showed that the risk of metabolic syndrome in schizophrenia was 3.7 (95% CI = 1.5 to 9.0). CONCLUSIONS: The high prevalence of metabolic syndrome in schizophrenia even at such a relatively young age underscores the need to select antipsychotic medications with no or little capability to induce metabolic side effects. Also, developing comprehensive efforts directed at controlling weight and diet and improving physical activity are needed.

Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort.

Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.

Adulthood mortality of infants isolated at birth due to tuberculosis in the family.

AIMS: In 1936 the Finnish Anti-Tuberculosis Association founded the first nursery, "Joulumerkkikoti", into which infants born into tuberculous families were admitted and given BCG vaccination to reduce the risk of tuberculosis. This prophylactic regimen was effective in reducing infant mortality and morbidity of tuberculosis. We investigated the mortality of these children later in childhood and adulthood. METHODS: The index cohort consisted of 3,020 subjects born between 1945 and 1965 in Finland and isolated from their family immediately after birth. The average separation time was 218 days. The subjects alive on 1 January 1971 were identified. For every index subject two reference subjects were chosen, the matching criteria being sex, year, and place of birth. Data on causes of deaths were obtained from the Finnish Cause of Death Registry by the end of 1998. RESULTS: The relative mortality rate (RR) was higher in the index cohort than in the reference cohort for all causes of death (RR 1.4; 95% CI 1.2-1.7), and particularly for unnatural deaths: RR 1.5 (1.1-1.9) for men and RR 1.9 (1.0-3.7) for women. CONCLUSIONS: The mortality in the index subjects later in childhood and adulthood was somewhat elevated. This may be explained by a variety of risks experienced during pregnancy, delivery, and childhood. The fall in the socioeconomic status of the family of origin due to tuberculosis may partially explain the result. Another interpretation is that the very early separation from the mother had unfavourable effects on later psychological developments in some children.