Associations between schizophrenia polygenic risk and apathy in schizophrenia spectrum disorders and healthy controls.

OBJECTIVE: Apathy is a central predictor of a poor functional outcome in schizophrenia. Schizophrenia polygenic risk scores (PRSs) are used to detect genetic associations to key clinical phenotypes in schizophrenia. We explored the associations between schizophrenia PRS and apathy levels in schizophrenia spectrum disorders (n = 281) and matched healthy controls (n = 298), and further how schizophrenia PRS contributed in predicting apathy when added to premorbid and clinical factors in the patient sample. METHOD: Schizophrenia PRSs were computed for each participant. Apathy was assessed with the Apathy Evaluation Scale. Bivariate correlation analyses were used to investigate associations between schizophrenia PRS and apathy, and between apathy and premorbid and clinical factors. Multiple hierarchical regression analyses were employed to evaluate the contributions of clinical variables and schizophrenia PRS to apathy levels. RESULTS: We found no significant associations between schizophrenia PRS and apathy in patients and healthy controls. Several premorbid and clinical characteristics significantly predicted apathy in patients, but schizophrenia PRS did not. CONCLUSION: Since the PRSs are based on common genetic variants, our results do not preclude associations to other types of genetic factors. The results could also indicate that environmentally based biological or psychological factors contribute to apathy levels in schizophrenia.

Psychotic patients who used cannabis frequently before illness onset have higher genetic predisposition to schizophrenia than those who did not.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) are heritable, polygenic disorders with shared clinical and genetic components, suggesting a psychosis continuum. Cannabis use is a well-documented environmental risk factor in psychotic disorders. In the current study, we investigated the relationship between SZ genetic load and cannabis use before illness onset in SZ and BD spectrums. Since frequent early cannabis use (age <18 years) is believed to increase the risk of developing psychosis more than later use, follow-up analyses were conducted comparing early use to later use and no use. METHODS: We assigned a SZ-polygenic risk score (PGRS) to each individual in our independent sample (N = 381 SZ spectrum cases, 220 BD spectrum cases and 415 healthy controls), calculated from the results of the Psychiatric Genomics Consortium (PGC) SZ case-control study (N = 81 535). SZ-PGRS in patients who used cannabis weekly to daily in the period before first illness episode was compared with that of those who never or infrequently used cannabis. RESULTS: Patients with weekly to daily cannabis use before illness onset had the highest SZ-PGRS (p = 0.02, Cohen's d = 0.33). The largest difference was found between patients with daily or weekly cannabis use before illness onset <18 years of age and patients with no or infrequent use of cannabis (p = 0.003, Cohen's d = 0.42). CONCLUSIONS: Our study supports an association between high SZ-PGRS and frequent cannabis use before illness onset in psychosis continuum disorders.

Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

Polygenic risk score and the psychosis continuum model.

OBJECTIVE: Schizophrenia (SZ) and bipolar disorder (BD) are heritable, polygenic disorders with shared clinical characteristics and genetic risk indicating a psychosis continuum. This is the first study using polygenic risk score (PGRS) to investigate the localization of diagnostic subcategories along the entire psychosis spectrum. METHOD: Based on results from the Psychiatric Genomics Consortium (PGC), we assigned a SZ and BD PGRS to each individual in our independent sample [N=570 BD spectrum cases, 452 SZ spectrum cases and 415 healthy controls (CTR)]. Potential differences in mean SZ and BD PGRS across diagnostic spectrums and subcategories were explored. RESULTS: SZ and BD PGRSs were significantly associated with both SZ and BD spectrums compared with CTR. For the subcategories, SZ PGRS was significantly associated with SZ, schizoaffective disorder, psychosis not otherwise specified, and BD1, while BD PGRS was significantly associated with BD1 and BD2. There were no significant differences between any of the diagnostic spectrums or subgroups for neither the SZ nor BD PGRS. Lifetime psychosis was significantly associated with SZ PGRS but not with BD PGRS. CONCLUSION: These findings further support the psychosis continuum model and provide molecular polygenetic validation of the localization of diagnostic subcategories within this continuum.

Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine.

BACKGROUND AND PURPOSE: Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman et al. (Nat Genet 2011: 43: 695-698), three common variants were found to confer risk of migraine at a genome-wide significant level (P < 5 × 10(-8) ). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic-based Danish and Icelandic cohort. METHODS: The top association SNPs were assessed in 2523 cases and 38,170 controls, and a meta-analysis was performed, combining the discovery set with all the follow-up studies. Finally the confirmed SNPs were assessed in a genotype-phenotype analysis. RESULTS: Two out of three SNPs that showed genome-wide significant associations in the previous study: rs10166942 (near TRPM8) and rs11172113 (in LRP1) were significantly associated with migraine in the present study. The meta-analysis confirmed the previous three genome-wide significant associated SNPs (rs2651899, rs10166942 and rs11172113) to confer risk of migraine. In addition, the C-allele of rs2078371 (near TSPAN-2) also reached genome-wide significance for association with migraine [OR = 1.14; CI = (1.09-1.20); P = 2.55 × 10(-8) ]. CONCLUSION: TSPAN-2 encodes an integral membrane protein involved in oligodendrogenesis. This new finding supports the plausible implication of neuroglia in the pathophysiology of MO and MTA.