Schizophrenia is a psychiatric disorder whose pathophysiology is largely unknown. It has a heritability of 60-80%, much of which is attributable to common risk alleles, suggesting genome-wide association studies can inform our understanding of aetiology. Here, in 69,369 people with schizophrenia and 236,642 controls, we report common variant associations at 270 distinct loci. Using fine-mapping and functional genomic data, we prioritise 19 genes based on protein-coding or UTR variation, and 130 genes in total as likely to explain these associations. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in autism and developmental disorder. Associations were concentrated in genes expressed in CNS neurons, both excitatory and inhibitory, but not other tissues or cell types, and implicated fundamental processes related to neuronal function, particularly synaptic organisation, differentiation and transmission. We identify biological processes of pathophysiological relevance to schizophrenia, show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provide a rich resource of priority genes and variants to advance mechanistic studies.

/pdf/mapping-genomic-loci-prioritises-genes-and-implicates-1klan2wiz1.pdf

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

OBJECTIVE
The objective of this study is to describe secular trends in the average age of death in patients with schizophrenia and to compare these with the general population.


METHODS
This is a longitudinal linkage study from 1 January 1980 to 31 December 2010 using the Danish Psychiatric Research Register and the Danish Cause of Death Register. Data were analyzed using descriptive statistics and survival analysis.


RESULTS
The average age of death in the schizophrenia population (62.2 years; 95% CI, 61.9-62.5) was lower compared to the general population (73.4 years; 95% CI, 73.4-73.4), P<0.001. In the general population we found, for men, an average increase in the age of death of 0.28 years (95% CI, 0.27-0.28) per calendar year, and for women an increase in age of death of 0.31 years (95% CI, 0.31-0.32) per calendar year (both P<0.001). In contrast, age of death decreased in the schizophrenia population: the change in average age of death for males was 0.04 years (95% CI, -0.09 to 0.00) per calendar year (P<0.05), and the comparable estimate for females was -0.05 years (95% CI, -0.09 to 0.01) per calendar year (P<0.05). A similar pattern existed after acts of self-harm as cause of death were excluded from the analyses. Patients diagnosed with schizophrenia had an increased mortality rate compared with the general population (hazard ratio, 2.05; 95% CI, 2.01-2.09).


CONCLUSIONS
On average, patients with schizophrenia die younger than the general population, independent of intentional self-harm as cause of death.

Increasing Mortality Gap for Patients Diagnosed with Schizophrenia

Antipsychotic use and risk of breast cancer in women with schizophrenia: a nationwide nested case-control study in Finland.

Invasive lobular carcinoma: an understudied emergent subtype of breast cancer

We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting. 

https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-022-02246-y

Systematic review of Mendelian randomization studies on risk of cancer

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study ...

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

Is Schizophrenia a Risk Factor for Breast Cancer?—Evidence From Genetic Data

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Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

Is Schizophrenia a Risk Factor for Breast Cancer?—Evidence From Genetic Data