American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

Irma Weinberg, a German-Jewish Neuropsychiatrist/Physician, authored the fourth report from the German Research Institute for Psychiatry in Munich examining the risk for dementia praecox (DP) in particular relatives of DP probands, here first-cousins. She examined 977 cousins of 54 DP probands and found a best-estimate risk of 1.4%. She conducted within-study analyses, showing a much higher risk for DP in the siblings than cousins of DP probands. She studied DP-related personalities showing a familial link between these conditions and risk for DP. She demonstrated that the risk for DP in cousins was impacted substantially by the distribution, in ancestors, of psychosis and personality abnormalities. After completing work on this article, Weinberg worked in private practice in Frankfurt, emigrating to the Netherlands in 1934, where she worked at a Jewish psychiatric hospital. In 1943, German occupiers evacuated the hospital, transporting the patients and staff, either directly to Auschwitz or, like Weinberg, to the Westerbork transit camp. On September 4, 1944, Dr. Weinberg was transported to Theresienstadt and soon thereafter to Auschwitz, where she was murdered at the age of 53. Her history raises painful questions about the relationship between genetic studies of psychiatric illness in prewar Germany and the Holocaust.

To date, bipolar disorder (BD) genetic studies and polygenic risk scores (PRSs) for BD are based primarily on populations of European descent (EUR) and lack representation from other ancestries including Latin American (LAT). Here, we describe a new LAT cohort from the Mayo Clinic Bipolar Biobank (MCBB), a multisite collaboration with recruitment sites in the United States (EUR; 1,443 cases and 777 controls) and Mexico and Chile (LAT; 211 cases and 161 controls) and use the sample to explore the performance of a BD-PRS in a LAT population. Using results from the largest genome-wide association study of BD in EUR individuals, PRSice2 and LDpred2 were used to compute BD-PRSs in the LAT and EUR samples from the MCBB. PRSs explained up to 1.4% (PRSice) and 4% (LDpred2) of the phenotypic variance on the liability scale in the LAT sample compared to 3.8% (PRSice2) and 3.4% (LDpred2) in the EUR samples. Future larger studies should further explore the differential performance of different PRS approaches across ancestries. International multisite studies, such as this one, have the potential to address diversity-related limitations of prior genomic studies and ultimately contribute to the reduction of health disparities.

Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan dataset. We defined a fetal effect score (FES) to quantify the involvement of each gene in prenatal brain development. We further employed the specificity indexes (SIs) to evaluate cell-type expression specificity from single-cell expression data in cerebral cortices of humans and mice. Compared with SCZ-commonGenes, SCZ-neuroGenes and SCZ-moduleGenes were highly expressed in the prenatal stage, had higher FESs, and had higher SIs in fetal replicating cells and undifferentiated cell types. Our results suggested that gene expression patterns in specific cell types in early fetal stages might have impacts on the risk of SCZ during adulthood.

For the return of polygenic risk scores to become an acceptable clinical practice in psychiatry, receipt of polygenic risk scores must be associated with minimal harm and changes in behavior that decrease one's risk for developing a psychiatric outcome. Data from a randomized controlled trial was used to assess the impact of different levels of hypothetical polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to change drinking behaviors. The analytic sample consisted of 325 participants recruited from an urban, public university. Results demonstrated that there were significant increases in psychological distress as the level of genetic risk for alcohol use disorder increased. In addition, the perceived chance of developing alcohol use disorder significantly increased as the level of genetic risk increased. Promisingly, a greater proportion of participants indicated that they would intend to engage in follow-up behaviors, such as seeking additional information, talking to a healthcare provider about risk, and reducing drinking behaviors, as the level of genetic risk increased. Returning polygenic risk scores for alcohol use disorder in a clinical setting has the potential to promote risk-reducing behavior change, especially with increasing levels of genetic risk. The study was registered on ClinicalTrials.gov (Identifier: NCT05143073).

On September 27, 1922, Ernst Rüdin gave an address to the Annual Conference of the German Society of Genetics entitled “Regarding the Heredity of Mental Disturbances.” Published in a 37-page article, Rüdin reviewed the progress in the field of Mendelian psychiatric genetics, then hardly more than a decade old. Topics included (a) the status of Mendelian analyses of dementia praecox and manic-depressive insanity which had expanded to include two and three locus and early polygenic models and sometimes included, respectively, schizoid and cyclothymic personalities; (b) a critique of theories for the explanation of co-occurrence of different psychiatric disorders within families; and (c) a sharp methodologic critique of Davenport and Rosanoff's contemporary work which emphasized Rüdin's commitment to careful, expert phenotyping, a primary focus on well-validated psychiatric disorders and not broad spectra of putatively inter-related conditions, and an emphasis on rigorous statistical modeling as seen in his continued collaboration with Wilhelm Weinberg.

Large numbers of genetic loci have been identified that are known to contain common risk alleles for schizophrenia, but linking associated alleles to specific risk genes remains challenging. Given that most alleles that influence liability to schizophrenia are thought to do so by altered gene expression, intuitively, case–control differential gene expression studies should highlight genes with a higher probability of being associated with schizophrenia and could help identify the most likely causal genes within associated loci. Here, we test this hypothesis by comparing transcriptome analysis of the dorsolateral prefrontal cortex from 563 schizophrenia cases and 802 controls with genome-wide association study (GWAS) data from the third wave study of the Psychiatric Genomics Consortium. Genes differentially expressed in schizophrenia were not enriched for common allelic association statistics compared with other brain-expressed genes, nor were they enriched for genes within associated loci previously reported to be prioritized by genetic fine-mapping. Genes prioritized by Summary-based Mendelian Randomization were underexpressed in cases compared to other genes in the same GWAS loci. However, the overall strength and direction of expression change predicted by SMR were not related to that observed in the differential expression data. Overall, this study does not support the hypothesis that genes identified as differentially expressed from RNA sequencing of bulk brain tissue are enriched for those that show evidence for genetic associations. Such data have limited utility for prioritizing genes in currently associated loci in schizophrenia.

Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the euchromatic histone methyl transferase 1 (EHMT1) gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota, an important modifier of the gut-brain-axis, may constitute an unexplored mechanism underlying clinical KS variation. We investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members, to test whether (1) variation in the gut microbiota associates with KS diagnosis and (2) variation within the gut microbiota relates with KS syndrome symptoms. Both alpha and beta diversity of patients were different from their family members. Genus Coprococcus 3 was lower in abundance in patients compared to family members. Moreover, abundance of genus Merdibacter was lower in patients versus family members, but only in participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% of beta diversity variance. Also, within this group, we detected higher levels of Atopobiaceae – uncultured and Ruminococcaceae Subdoligranulum associated with higher symptom severity. These significant signatures in the gut microbiota composition in patients with KS suggest that microbiota differences are part of the KS phenotype.

Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co-segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.

Tourette syndrome (TS) is caused by multiple genetic and environmental factors. Yet, little is known about the interplay of these factors in the occurrence of tics. We investigated whether polygenic risk score (PRS) of TS and pregnancy-related factors together enhance the explained variance of tic occurrence in the Avon Longitudinal Study of Parents and Children (N_cases = 612; N_controls = 4,201; 50% male; mean age 13.8 years). We included a cumulative adverse pregnancy risk score, maternal anxiety and depression, and maternal smoking and alcohol use during pregnancy. We investigated possible joint effects of genetic and pregnancy-related risk factors using a multivariable approach, and explored mediation effects between the pregnancy-related risk factors in explaining tic presence. The PRS and the cumulative adverse pregnancy risk score, maternal anxiety, or maternal depression explained significantly more variance of tic presence compared to models including only the PRS. Furthermore, we found that the cumulative adverse pregnancy risk score mediated the association between several pregnancy-related factors (maternal anxiety, depression, and smoking) and tics. The combination of a PRS and pregnancy-related risk factors explained more variance of tics in a general population cohort compared to studying these factors in isolation.