Schizophrenia polygenic risk score in psychosis proneness.

Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ.

Sex-specific association between schizophrenia polygenic risk and subclinical schizophrenia-related traits.

BACKGROUND: According to the dimensional view of psychiatric disorders, psychosis is expressed as a continuum in the general population. However, the investigation of the putative genetic aetiological continuity between its clinical and subclinical phenotypes has yielded mixed results. We aimed to replicate previous findings regarding the association of polygenic risk for schizophrenia with subclinical traits (i.e., schizotypy traits and psychotic-like experiences), and to examine the role of sex in this association in a large nonclinical sample. METHODS: The Multidimensional Schizotypy Scale and the Community Assessment of Psychic Experiences were assessed in 919 nonclinical participants. Polygenic Risk Scores for schizophrenia (SZ-PRSs) were computed using the PRS-CS method based on the latest genome-wide association study of schizophrenia. Summary statistics derived from the total GWAS sample and stratified by sex were used. Linear regression analyses tested the associations of the SZ-PRSs with the psychometric variables, both in the total sample and by sex. RESULTS: No associations were found between the SZ-PRSs and the positive, negative or disorganized dimensions of schizotypy in the total sample. Likewise, no associations were found with psychotic-like experiences. However, the sex-stratified analyses revealed a male-specific association with positive schizotypy. Similar results were obtained with the PRSs derived from the sex-stratified summary statistics. DISCUSSION: Our results are consistent with the lack of clear evidence of an association between SZ common genetic risk and its subclinical phenotypes. Nevertheless, the male-specific association found suggests that this PRS might explain better the male phenotype, as reported in previous studies. Future studies should put a focus on the role of sex in this association to unravel its sex specificities.

Use of polygenic risk scores to assess weight loss after bariatric surgery: a 5-year follow-up study.

BACKGROUND: Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes suggests a moderating effect of several factors, including individual genetic background. This study aimed to investigate the contribution of the genetic architecture of body mass index (BMI) to the variability in weight loss outcomes after BS. METHODS: A total of 106 patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy were followed up for 5 years. Changes in BMI (BMIchange) and percentage of total weight loss (%TWL) were evaluated during the postoperative period. Polygenic risk scores (PRSs), including 50 genetic variants, were calculated for each participant to determine their genetic risk of high BMI based on a previous genome-wide association study. Generalized estimating equation models were used to study the role of the individual's polygenic score and other factors on BMIchange and %TWL in the long term after surgery. RESULTS: This study found an effect of the polygenic score on %TWL and BMIchange, in which patients with lower scores had better outcomes after surgery than those with higher scores. Furthermore, when analyzing only patients who underwent RYGB, the results were replicated, showing greater weight loss after surgery for patients with lower polygenic scores. DISCUSSION: Our results indicate that genetic background assessed with PRSs, along with other individual factors, such as biological sex, age, and preoperative BMI, has an effect on BS outcomes and could represent a useful tool for estimating surgical outcomes in advance.

Genetic risk score based on obesity-related genes and progression in weight loss after bariatric surgery: a 60-month follow-up study.

BACKGROUND: Obesity is a polygenic multifactorial disease. Recent genome-wide association studies have identified several common loci associated with obesity-related phenotypes. Bariatric surgery (BS) is the most effective long-term treatment for patients with severe obesity. The huge variability in BS outcomes between patients suggests a moderating effect of several factors, including the genetic architecture of the patients. OBJECTIVE: To examine the role of a genetic risk score (GRS) based on 7 polymorphisms in 5 obesity-candidate genes (FTO, MC4R, SIRT1, LEP, and LEPR) on weight loss after BS. SETTING: University hospital in Spain. METHODS: We evaluated a cohort of 104 patients with severe obesity submitted to BS (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for >60 months (lost to follow-up, 19.23%). A GRS was calculated for each patient, considering the number of carried risk alleles for the analyzed genes. During the postoperative period, the percentage of excess weight loss total weight loss and changes in body mass index were evaluated. Generalized estimating equation models were used for the prospective analysis of the variation of these variables in relation to the GRS. RESULTS: The longitudinal model showed a significant effect of the GRS on the percentage of excess weight loss (P = 1.5 × 10-5), percentage of total weight loss (P = 3.1 × 10-8), and change in body mass index (P = 7.8 × 10-16) over time. Individuals with a low GRS seemed to experience better outcomes at 24 and 60 months after surgery than those with a higher GRS. CONCLUSION: The use of the GRS in considering the polygenic nature of obesity seems to be a useful tool to better understand the outcome of patients with obesity after BS.