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

The missense SNP NC_000004.12:g.102267552C>T (also known as SLC39A8.p.(Ala391Thr), rs13107325) in SLC39A8 encodes a zinc transporter. This SNP has been linked to schizophrenia and is the likely causal variant for one of the genome-wide association loci associated with the disorder. Using regression analyses, we tested whether the schizophrenia-risk allele at p.(Ala391Thr) was associated with schizophrenia-related phenotypes, including positive, negative, and disorganized symptoms, cognitive ability, educational attainment, and age of psychosis onset, within three schizophrenia cohorts (combined N = 1232) and, with equivalent phenotypes, in a sample of population controls (UK Biobank, N = 355,069). We also used the population controls to test for associations with rare protein-truncating and deleterious missense variants within SLC39A8. Within the schizophrenia cohorts, after correction for multiple testing, p.(Ala391Thr) was not significantly associated with any schizophrenia-related phenotypes. In the unaffected participants from the UK Biobank, the schizophrenia-risk allele at p.(Ala391Thr) was associated with significantly poorer cognitive ability and fluid intelligence, a lower probability of obtaining GCSEs or a degree-level qualification, and fewer years in education. There was no association between p.(Ala391Thr) and self-reported psychotic experiences in this cohort. Rare variants in SLC39A8 were nominally associated with poorer cognitive ability, but these associations did not survive correction for multiple testing. The schizophrenia-risk allele was associated with poorer cognitive ability, but not psychotic experiences, in a volunteer sample drawn from the general population. We found no evidence that p.(Ala391Thr) was associated with symptom severity in schizophrenia. To understand the impact of rare variants in SLC39A8 on cognitive impairment, larger independent samples are required.

Treatment-resistant mood disorders are often managed with intensive interventions that include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), ketamine, and esketamine, but the role of genetics in clinical response to those interventions is yet to be clearly determined. Here, we review the current literature on the genetics of response to these treatment modalities. To date, the limited number of studies done to investigate genetic predictors of treatment response have primarily focused on single variants in candidate genes, and none of these have been consistently reproducible. The majority of candidate gene studies examine the effect of variants in the COMT and BDNF genes on treatment response. There are a limited number of genome-wide association studies (GWAS) looking at treatment response, though they are almost all underpowered, with only one study including a sample size > 1000. As a result, there have been few single nucleotide polymorphisms (SNPs) found to be associated with treatment response at a statistically significant level, all in genes other than COMT and BDNF. The challenge is now to generate data from a large group of patients undergoing these therapies in order to more robustly assess the genetic factors affecting treatment response. This will not only help establish genetic predictors of response, but also potentially develop differential predictors of response to available treatments, which could provide clinicians with critical information to aid in deciding which treatment modality to recommend for treatment-resistant depression. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ic consortium.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause. This prospective study aimed to explore the utility of genome sequencing to identify additional molecular diagnoses that may contribute to variability in a cohort of patients with PMS. Twenty probands diagnosed with PMS (60% with a 22q13 deletion, 40% with a SHANK3 variant) underwent trio or duo genome sequencing and chromosomal microarray. This analysis identified a second molecular finding associated with a neurological condition in 3/20 participants. Molecular diagnoses related to neurological phenotypes included: (1) spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant (SMALED2A), (2) spastic paraplegia 7, and (3) 16p11.2 deletion syndrome. Five additional new molecular diagnoses were associated with a clinically actionable secondary or incidental finding. This exploratory study provides early evidence for the potential utility of expanded sequencing among individuals with PMS, even for those without phenotypic features outside of the expected range.

The research of single gene-related disorders or pathogenic copy-number variations (CNVs) has given a significant impetus to the shift from a diagnostic work-up focused on epileptic syndromes to genomic approaches in individuals with severe pediatric-onset epilepsies and in developmental and epileptic encephalopathies. Genome-wide association studies (GWAS) have identified various loci of susceptibility for common epilepsies and highlighted a strong predisposing role of common variants in several genes involved in well-known monogenic diseases. The largest GWAS identified eight major loci with stronger genome-wide significance for epilepsy, regardless the underlying epileptic syndrome: 2q24.3, 2p16.1, 4p15.1, 7q21.11, 8p23.1, 9q21.13, 10q24.32, 16q12.1, 2p16.1 and 2q24.3 occurred more frequently in patients with genetic generalized epilepsies. Loci 4p12, 8q23.1 and 16p11.2 achieved a high genome-wide significance for Juvenile Myoclonic Epilepsy. Childhood Absence Epilepsy was significantly genome-wide associated with 2p16.1 and 2q22.3. The loci 3q25.31, 6q22.31 and 2q24.3 were significantly associated with non-acquired focal epilepsies. Polygenic risk scores (PRS) are used to quantify the cumulative effects of several common genetic variants in a single score, each of which individually contributes minimally to disease susceptibility. The impact of PRS on clinical practice might be relevant for epilepsy risk prediction in groups of patients at high risk of developing epilepsy in the near future. Elevated PRS values have been observed in genetic generalized epilepsies particularly in familial forms, females, and patients with previous seizure events. Among comorbidities associated with epilepsy, depression, psychosis, and attention-deficit/hyperactivity disorder (ADHD) showed significantly elevated PRS.

Trichotillomania (TTM) is a psychiatric condition in which people feel an overwhelming urge to pull out their hair, resulting in noticeable hair loss and significant distress. Twin and family studies suggest that TTM is at least partly genetic, but no genome-wide analyses have been completed. To fill the gap in this field, we have conducted a case–control study of genotype array data from 101 European ancestry TTM cases and 488 ancestry-matched unaffected controls. TTM cases were ascertained in the United States through web-based recruitment, patient support groups, and conferences organized by the Trichotillomania Learning Center. Following clinical confirmation of a TTM diagnosis, patients completed self-report assessments of frequency and duration of hair pulling, other psychiatric symptoms, and family history. Unaffected controls were also ascertained in the United States and were matched to cases by ancestry. In the first formal genome-wide association study of TTM, we did not identify any common variants with a genome-wide significant (p < 5 × 10⁻⁸) association level with case status. We found that cases carry a higher load of common polygenic risk for psychiatric disorders (p = 0.008). We also detected copy number variants previously associated with neuropsychiatric disorders (specifically, deletions in NRXN1, CSMD1, and 15q11.2). These results further support genetics' role in the etiology of TTM and suggest that larger studies are likely to identify risk variation and, ultimately, specific risk genes associated with the condition.

Women with the FMR1 premutation (FXpm) are at heightened genetic vulnerability for depression, with risk compounded by the stressors of parenting a disabled child. Although risk factors persist as FXpm women age, depression in FXpm mothers during midlife and old age is poorly characterized. This study used an accelerated longitudinal design to capture the trajectory of depressive symptoms in 73 FXpm mothers across 20–75 years of age. The FXpm mothers had children with fragile X syndrome or FXpm and contributed 2–11 longitudinal assessments, for a total of 294 observations. Mothers with mid-range CGG expansions (91–110 CGG repeats) exhibited the highest overall symptoms, with a marked increase in depression during early midlife, followed by late midlife trajectories that varied by history of premature menopause. Symptoms of mothers with high CGGs (111–200) peaked during early and late adulthood rather than midlife. At low CGGs (55–90) symptoms were low and stable across age. Parenting stress was associated with increased symptoms during early adulthood, but this effect dwindled with age. Findings illuminate evolving patterns of depression vulnerability across adulthood that are shaped by specific environmental and genetic factors, offering insights for personalized medicine to enhance the health of aging FXpm mothers.

A large proportion of patients undergoing cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) do not respond sufficiently to treatment. Identifying predictors for change in symptom severity after treatment could inform clinical decision-making, allow for better-tailored interventions, and avoid treatment failure. Prior research on predictors for treatment response has, however, yielded inconsistent findings with limited clinical utility. Here, we investigated the predictive power of nine polygenic risk scores (PRSs) for psychiatric and cognitive traits in 1598 OCD patients (1167 adults and 431 children/adolescents) treated with CBT in Sweden and Norway. We fitted linear mixed models adjusted for age, sex, genotyping batch, and the first five ancestry PCs to estimate associations between PRS and symptom severity change from pre- to post-treatment. The PRS for schizophrenia showed a modestly significant association with symptom change (β = 0.013, p = 0.04, R ² = 0.10), indicating that a higher PRS for schizophrenia was associated with a smaller decrease in symptom severity. No other PRS were significantly associated with the outcome. While these results await replication and expansion, current PRS for psychiatric and cognitive phenotypes do not seem to contribute meaningfully to symptom severity change in CBT for OCD.