No abstract

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance. Using a two-stage strategy for another complex disorder, a number of putative IDDM-susceptibility genes have recently been mapped. We now report the results of a two-stage genome-wide search for genes conferring susceptibility to schizophrenia. In stage I, model-free linkage analyses of large pedigrees from Iceland, a geographical isolate, revealed 26 loci suggestive of linkage. In stage II, ten of these were followed-up in a second international collaborative study comprising families from Austria, Canada, Germany, Italy, Scotland, Sweden, Taiwan and the United States. Potential linkage findings of stage I on chromosomes 6p, 9 and 20 were observed again in the second sample. Furthermore, in a third sample from China, fine mapping of the 6p region by association studies also showed evidence for linkage or linkage disequilibrium. Combining our results with other recent findings revealed significant evidence for linkage to an area distal of the HLA region on chromosome 6p. However, in a fourth sample from Europe, the 6p fine mapping finding observed in the Chinese sample could not be replicated. Finally, evidence suggestive of locus heterogeneity and oligogenic transmission in schizophrenia was obtained.

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 -50, P < 2.14 x 10 -6 ), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that proteintruncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.

The Taiwan Psychiatric Epidemiological Project, conducted from 1982 to 1986, used the multistage random sampling method with 5005, 3004 and 2995 subjects selected respectively from metropolitan Taipei (MT), 2 small towns (ST) and 6 rural villages (RV). The case identification tool was the Chinese modified Diagnostic Interview Schedule (DIS-CM). This study presents the lifetime and one-year prevalence of 27 and of 17 specific psychiatric disorders respectively. The lifetime prevalence of any disorder defined by the DIS-CM -- excluding tobacco dependence -- was 16.3%, 28.0% and 21.5% in the MT, ST and RV samples respectively. The differences in lifetime prevalence between the sexes and between the 3 sampling areas were significant for 15 and 8 disorders respectively. The ST sample seemed to have the most disorders, with the highest prevalence among 3 sampling areas. The mean ratio of one-year to lifetime prevalence was 0.67. The differences in prevalence rates between the 3 sampling areas and between the international studies are discussed from methodological, social and cultural points of view.

79 80 * These authors contributed equally to the work 81 §These authors jointly supervised the work 82 †Lists of participants and their affiliations appear in the Supplementary Information 83 84 85 86Finally, polygenic risk score (PRS) prediction is emerging as a useful tool for studying 129 the effects of genetic liability, identifying more homogeneous phenotypes, and stratifying 130 patients, but the applicability of training data from EUR studies to those of non-European 131 ancestry has not been fully assessed, leaving us with an uncertainty as to the biological 132 implications and utility in non-Europeans 20 . 133 134 Schizophrenia genetic associations in the East Asian populations 135To systematically examine the genetic architecture of schizophrenia in individuals of East Asian 136 ancestry (EAS), we compiled 22,778 schizophrenia cases and 35,362 controls from 20 samples 137

Panic disorder is relatively consistent, with a few exceptions, in rates and patterns across different countries. It is unclear why the rates of panic and other psychiatric disorders are lower in Taiwan.