Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder.

Objectives: Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism.

Methods: A genome-wide allelic association study of 506 patients from the University College London bipolar disorder case-control sample and 510 ancestrally matched supernormal controls.

Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes.

Objective: There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present.

Yin yang haplotypes revisited - long, disparate haplotypes observed in European populations in regions of increased homozygosity.

Objectives: Yin yang haplotypes differ at every SNP. A previous study provided striking examples of these haplotypes, but claimed that their distribution across the genome could be attributed to chance. When we studied regions of homozygosity (ROHs) we found haplotypes that tended to differ at several SNPs simultaneously but did not subject this to formal testing.

No evidence for excess runs of homozygosity in bipolar disorder.

Background: Recent studies have reported large common regions of homozygosity (ROHs) that are the result of autozygosity, that is, the cooccurrence within individuals of long haplotypes that have a high frequency in the population. A recent study reports that such regions are found more commonly in individuals with schizophrenia compared with controls, and identified nine 'risk ROHs' that were individually more common in cases. Of these, four contained or neighboured genes associated with schizophrenia (NOS1AP/UHMK1, ATF2, NSF and PIK3C3).

Markers typed in genome-wide analysis identify regions showing deviation from Hardy-Weinberg equilibrium.

Background: Deviations from Hardy-Weinberg equilibrium (HWE) are commonly thought of as indicating genotyping errors, population stratification or some other artefact. However they could also arise through important biological mechanisms. In particular, genetic variants having a recessive effect on the successful fertilisation and/or development of an embryo might be manifest through such deviations in an unselected sample of "control" subjects.

A simple method for assessing the strength of evidence for association at the level of the whole gene.

Introduction: It is expected that different markers may show different patterns of association with different pathogenic variants within a given gene. It would be helpful to combine the evidence implicating association at the level of the whole gene rather than just for individual markers or haplotypes. Doing this is complicated by the fact that different markers do not represent independent sources of information.

A pragmatic suggestion for dealing with results for candidate genes obtained from genome wide association studies.

Background: Researchers may embark on a genome-wide association study before fully investigating candidate regions which have been reported to produce evidence to suggest that they harbour susceptibility loci. If the genome wide study had not been carried out then results which demonstrated only modest statistical significance from candidate regions would be judged to be of interest and would stimulate further investigation. However if hundreds of thousands of markers are typed then inevitably very large numbers of such results will occur by chance and those from candidate regions may attract no special attention.