Common variants conferring risk of schizophrenia

By Hreinn Stefansson, Roel A. Ophoff, S. Steinberg, O. Andreassen, S. Cichon, D. Rujescu, T. Werge, O. Pietiläinen, O. Mors, P. Mortensen and 77 more. Nature, 2009

1,753 citations recorded by the source corpus.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/a8980ddb3b83d6a139543463c9c1b18d307a9338

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Citations in the corpus

The role of immune dysfunction in the pathophysiology of autism (2011, positive): “…twins, while concordance rates of 44–91% are reported for monozygotic twins (Bailey et al., 1995; Constantino and Todd, 2000; Kates et al., 2004; Steffenburg et al., 1989), suggesting that genetic composition may contribute to ll rights reserved. icrobiology and Immunology, isorders (M.I.N.”
Fast and accurate long-range phasing in a UK Biobank cohort (2015, positive): “LRP has been successfully used in the Icelandic population to rapidly determine highly accurate phase and impute rare variants, producing insights into fine-scale recombination and enabling dozens of discoveries regarding numerous diseases [14–27].”
Spatiotemporal transcriptome of the human brain (2011, background): “( GDA ) and to schizophrenia and affective disorder”
Developing constructs for psychopathology research: research domain criteria. (2010, positive): “Nevertheless, a variety of recent studies have noted considerable overlaps in familial and genetic risk (International Schizophrenia Consortium, 2009; Losh, Sullivan, Trembath, & Piven, 2008; Stefansson et al., 2009).”