Background

Many psychiatric disorders display distinct sex differences. Men are more likely to be affected by neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. ADHD is a childhood onset disorder characterised by inattention, overactivity and impulsiveness. The disorder affects males more than females at a ratio of 4:1. In schizophrenia, the age of onset in men is significantly earlier (21 years) than for women (25 years). The disorder is more severe in male patients and they generally have more negative symptoms (Preston et al, 2002).

The causes of sex differences in neurodevelopmental disorders could be due to endocrine, genetic, or environmental factors and their possible interactions. In terms of genetic factors men and women differ in their sex chromosome complement and therefore the Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders.

Animal studies where it has been possible to disaggregate gonadal sex and sex chromosome complement have found that the Y chromosome is associated with more aggressive and less parental behaviour (De Vries et al, 2002; Gatewood et al, 2006). Possession of two Y chromosomes as in the chromosomal abnormality XYY is associated with a higher risk of antisocial behaviour when compared to those with an XXY chromosomal anomaly (Rutter et al, 2003).

However, there are difficulties in studying the Y chromosome: there is no recombination, no widely accepted nomenclature and its distribution depends highly on geographic origin (Jobling and Tyler-Smith, 2003). These difficulties have led to the Y chromosome being largely excluded from genetic and genomic studies of neuropsychiatric disorders.

To overcome this lack of knowledge surrounding the Y chromosome in psychiatric disorders, we chose to study Y chromosome variants in a sample of 210 cases with ADHD, 310 cases with schizophrenia and 700 U.K. controls.

Our hypothesis is that:

* Y chromosome haplogroups increase male susceptibility to ADHD and SZ directly

* Y chromosome haplogroups increase male susceptibility to ADHD and SZ indirectly by interacting with autosomal genes expressed in brain or environmental factors

* Y chromosome haplogroups influence sexually dimorphic cognitive performance which has a modifying effect on the disorders

Y chromosome SNPs were selected after extensive research on markers used in previous Y chromosome studies, Y chromosome Consortium data, which contain information on all the Y chromosome haplogroups (groups of haplotypes), and personal communication with research experts on the Y chromosome. These SNPs were selected in order to capture the most frequent Y chromosome haplogroups in the U.K.

Statistical analysis of Y chromosome haplogroups revealed no significantly increased representation of any haplogroup in cases with ADHD (p=0.539) or schizophrenia (p=0.679) compared to controls.