Cardiovascular disease, psychiatric diagnosis and sex differences in the multistep hypothesis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) risk increases with age, and a linear log-incidence and log-age relationship is interpreted to suggest that five to six factors are involved in disease onset. The factors remain unidentified, except that fewer steps are predicted for those carrying a known ALS-causing mutation. METHODS: Men with a psychiatric disorder or cardiovascular disease (CVD) diagnosis have an increased relative risk of ALS. Using the Danish population registries and ALS diagnosis years 1980 to 2017, we tested whether these factors would decrease the predicted steps to disease. RESULTS: Consistent with previous reports, we find a linear log-incidence and log-age ALS-onset relationship (n = 4385, regression coefficient b = 4.6, 95% confidence interval [CI]: 4.3-4.9, R2  = 0.99). This did not differ when considering ALS cases with a prior psychiatric diagnosis (n = 391, b = 4.6, 95% CI: 4.0-5.1) Surprisingly, it was higher (+1.5 steps, P = 2.3 × 10-5 ) for those with a prior CVD diagnosis (n = 901, b = 6.1, 95% CI: 5.4-6.8). To control for competing risk of death, a test to investigate if this effect was maintained in those with CVD in the population demonstrated an increased baseline risk and fewer steps to disease (b = 1.8, 95% CI: 1.2-2.3, P = 4.6 × 10-21 ), which consistent with a positive association of CVD and ALS. Assessing sex differences, our data and meta-analyses (n = 22 495) support half a step fewer for men (-0.4, 95% CI: ±0.24, P = 0.00031) without support for contributing differences explained by menopause. CONCLUSIONS: Any factor associated with ALS disease onset may be relevant for understanding disease pathogenesis and/or counselling. Modelling disease incidence with age demonstrates some insight into relevant risk factors; however, the outcome can differ if competing risks are considered.

The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark.

BACKGROUND: Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. METHODS: Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. RESULTS: Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). CONCLUSIONS: While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.

High loading of polygenic risk in cases with chronic schizophrenia.

Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.

Parental history of psychiatric diagnoses and unipolar depression: a Danish National Register-based cohort study.

BACKGROUND: Depression is known to run in families, but the effects of parental history of other psychiatric diagnoses on depression rates are less well studied. Few studies have examined the impact of parental psychopathology on depression rates in older age groups. METHOD: We established a population-based cohort including all individuals born in Denmark after 1954 and alive on their 10th birthday (N = 29 76 264). Exposure variables were maternal and paternal history of schizophrenia, bipolar disorder, depression, anxiety or 'other' psychiatric diagnoses. Incidence rate ratios (IRRs) were estimated using Poisson regressions. RESULTS: Parental history of any psychiatric diagnosis increased incidence rates of outpatient (maternal: IRR 1.88, p < 0.0001; paternal: IRR 1.68, p < 0.0001) and inpatient (maternal: IRR 1.99, p < 0.0001; paternal: IRR 1.83, p < 0.0001) depression relative to no parental history. IRRs for parental history of non-affective disorders remained relatively stable across age groups, while IRRs for parental affective disorders (unipolar or bipolar) decreased with age from 2.29-3.96 in the youngest age group to 1.53-1.90 in the oldest group. IRR estimates for all parental diagnoses were similar among individuals aged ⩾41 years (IRR range 1.51-1.90). CONCLUSIONS: Parental history of any psychiatric diagnosis is associated with increased incidence rates of unipolar depression. In younger age groups, parental history of affective diagnoses is more strongly associated with rates of unipolar depression than non-affective diagnoses; however, this distinction disappears after age 40, suggesting that parental psychopathology in general, rather than any one disorder, confers risk for depression in middle life.