Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

DNA content from 8 different donors.

<p>DNA content from 8 different donors.</p

Confocal microscopy overlays of autofluorescence scans (green) and the respective positive cell surface and intracellular antibody (red) staining, 20 µm cryocuts, scale bars equal (A,B,C) 50 µm, (D) 150 µm.

<p>(<b>A</b>) Anti. α-Catenin (<b>B</b>) Anti- Cytokeratin (<b>C</b>) Anti- vWF (<b>D</b>) Anti- VEGFR1</p

Confocal microscopy: (A-D) Confocal microscopy autofluorescence images of 20 µm ADM cryocuts, scale bars equal (A,C) 75 µm, (B,D) 50 µm; (D) the white arrow indicates a putative vessel channel; (E,F) autofluorescence images of 10 µm cryocuts of native human skin, scale bars equal (E,F) 75 µm.

<p>Confocal microscopy: (A-D) Confocal microscopy autofluorescence images of 20 µm ADM cryocuts, scale bars equal (A,C) 75 µm, (B,D) 50 µm; (D) the white arrow indicates a putative vessel channel; (E,F) autofluorescence images of 10 µm cryocuts of native human skin, scale bars equal (E,F) 75 µm.</p

Confocal microscopy overlays of autofluorescence scans (green) and the respective anti- matrix antibody staining (blue); comparison of 20 µm cryocuts of ADM (A,C,E,G,I,K) and 10 µm cryocuts of native human skin (B,D,F,H,J,L); scale bars equal 150 µm.

<p>(<b>A,B</b>) anti- collagen I (<b>C,D</b>) anti- collagen III (<b>E,F</b>) anti- collagen IV (<b>G,H</b>) anti- laminin 1 (<b>I,J</b>) anti- fibronectin (<b>K,L</b>) anti- hyaluronic acid.</p

Biomechanical results of the two available sizes <i>thin</i> and <i>thick</i> of the ADM; Values are presented as mean (SD), <i>P</i>- Value evaluate significances between the differences of properties of the different sizes.

<p>Biomechanical results of the two available sizes <i>thin</i> and <i>thick</i> of the ADM; Values are presented as mean (SD), <i>P</i>- Value evaluate significances between the differences of properties of the different sizes.</p

Gelelectrophoresis - DNA from 8 different donors, as DNA marker a 100bp DNA ladder was used.

<p>Gelelectrophoresis - DNA from 8 different donors, as DNA marker a 100bp DNA ladder was used.</p

Influence of pores on cell proliferation.

<p>Comparison between (<b>A</b>) unirradiated group 1 (+por-rad) and group 2 (-por-rad) and (<b>B</b>) irradiated group 3 (+por+rad) and group 4 (-por+rad) respectively with and without pores. All values are expressed as mean values ± standard deviation.</p

Influence of radiation on cell proliferation.

<p>Comparison between (<b>A</b>) porous group 1 (+por-rad) and group 3 (+por+rad) and (<b>B</b>) non-porous group 2 (-por-rad) and group 4 (-por+rad) respectively with and without radiation. All values are expressed as mean values ± standard deviation.</p