Recently in Molecular Psychiatry, Priebe and colleagues reported a genomewide search for copy number variants (CNVs) in subjects with bipolar disorder and healthy control subjects. The results tie CNVs to early, but not later-onset bipolar disorder. This is the first study that partially supports our initial finding of increased rare CNVs in early-onset bipolar disorder (Zhang et al., 2009). But they failed to replicate an overall burden of rare CNVs in bipolar. We say that it is only partial support is because Priebe et al. found CNV burden is primarily from microduplications; in contrast, our reported burden was primarily from singleton deletions.

An overall rare CNV burden has been questioned by two other papers which analyzed WTCCC data (Grozeva et al., 2010; WTCCC, 2010). These data have a less-than-ideal genotyping platform, and exclude more CNVs from their analysis than the two later papers. The new study by Priebe et al. used...  Read more

Recently in Molecular Psychiatry, Priebe and colleagues reported a genomewide search for copy number variants (CNVs) in subjects with bipolar disorder and healthy control subjects. The results tie CNVs to early, but not later-onset bipolar disorder. This is the first study that partially supports our initial finding of increased rare CNVs in early-onset bipolar disorder (Zhang et al., 2009). But they failed to replicate an overall burden of rare CNVs in bipolar. We say that it is only partial support is because Priebe et al. found CNV burden is primarily from microduplications; in contrast, our reported burden was primarily from singleton deletions.

An overall rare CNV burden has been questioned by two other papers which analyzed WTCCC data (Grozeva et al., 2010; WTCCC, 2010). These data have a less-than-ideal genotyping platform, and exclude more CNVs from their analysis than the two later papers. The new study by Priebe et al. used Illumina’s HumanHap550v3 (HH550) or Human610-Quadv1 (H610Q) BeadArrays, which would produce more reliable CNV calls. Quality control and statistical methods also differed among these studies.

Putting this together, it seems that rare CNVs do play a role in bipolar disorder. But the overall burden of CNVs for later-onset bipolar is still questionable. It is expected that CNV studies with more focus on early-onset bipolar disorder, and using higher-resolution methods such as deep-coverage next-generation sequencing, on more samples, will be necessary to resolve the role of rare CNVs in bipolar. In any case, we are still in need of methods to take us from the CNV burden into identification of specific genes responsible for illness.

References:

Zhang D. et al. Singleton Deletions Throughout the Genome Increase Risk of Bipolar Disorder. Mol Psychiatry. 2009 April; 14(4): 376–380. Abstract

Grozeva D et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2010 Apr;67(4):318-27. Abstract

WTCCC. Genomewide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010 Apr 1;464(7289):713-20. Abstract