Pleiotropic effects on psychopathology (Lancet 2013)

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
Lancet. 2013 Apr 20;381(9875):1371-9.
http://www.ncbi.nlm.nih.gov/pubmed/23453885
Cross-Disorder Group of the Psychiatric Genomics Consortium.
Erratum in: Lancet. 2013 Apr 20;381(9875):1360.

BACKGROUND:
Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories.
We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

METHODS:
We analyzed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders

FINDINGS:
SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2.
Model selection analysis supported effects of these loci for several disorders.
Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity.
Pathway analysis supported a role for calcium channel signalling genes for all five disorders.

INTERPRETATION:
Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology.
These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

cited by:
Genes and the Human Condition (From Behavior to Biotechnology)
Coursera 2014
https://www.coursera.org/course/genes

Brain changes precede schizophrenia and autism

In children with certain gene variants, symptoms similar to common learning disabilities could be omens of serious psychiatric conditions.

Brain changes precede schizophrenia and autism
Carriers of high-risk genes show cognitive impairments and could benefit from early intervention.
18 December 2013
http://www.nature.com/news/brain-changes-precede-schizophrenia-and-autism-1.14415

People who carry high-risk genetic variants for schizophrenia and autism have impairments reminiscent of disorders such as dyslexia, even when they do not yet have a mental illness, a new study has found.
The findings offer a window into the brain changes that precede severe mental illness and hold promise for early intervention and even prevention.

Rare genetic alterations called copy number variants (CNVs), in which certain segments of the genome have an abnormal number of copies, play an important part in psychiatric disorders: Individuals who carry certain CNVs have a several-fold increased risk of developing schizophrenia or autism.
But previous studies were based on individuals who already have a psychiatric disorder, and until now, no one had looked at what effects these CNVs have in the general population.
people with these variants but no diagnosis of autism or a mental illness still show subtle brain changes and impairments in cognitive function.

People carrying the variants performed worse than controls from the general population on cognitive tests and measures of general day-to-day functioning, and they were more likely to show a history of various learning disabilities.
For instance, carriers of one particular CNV, a deletion in a specific region of chromosome 15, tend to have a history of dyslexia and a difficulty in understanding numbers.
MRI showed that the same deletion alters brain structure in a way also seen in individuals with early stages of psychosis, and in individuals with dyslexia.

“It’s not as if [the variants] are just one incremental factor in your risk for psychosis … “They actually are impacting cognition in a significant way.”