The role of GPR161 and its modifiers in spina bifida: association studies in a human cohort.

Spina bifida is a complex disease trait underlying multiple genetic and
environmental factors. We recently demonstrated that the spina bifida phenotype
in the vacuolated lens (vl) mouse is due to a mutation in Gpr161, a gene
encoding a previously uncharacterized orphan G protein coupled receptor (GPCR).
As we observed modification of the phenotype characteristic for vl we concluded
that modifier genes are present. Subsequent analysis identified six modifier
loci.

Now that we have identified the gene underlying the vl mutation and have strong
candidates for its genetic modifiers in mouse, we want to investigate their
role in human spina bifida. Therefore, our aim is to test GPR161 and its
modifier loci for association with spina bifida in human.

To enable gene association testing in human, we will set up a cohort of 500
spina bifida patients and their parents. Using a parent-parent-affected
offspring trio design has the advantage that it has more power to detect
association, is immune for population stratification, enables the construction
of haplotypes, and allows (in part) for checking of genotype errors compared to
a case-control design.

Participants are asked to donate blood for DNA isolation (neonates 4 ml; all
other participants 10 ml). There is no risk related to participation. Since
neonates with spina bifida are planned for operation, blood withdrawal can be
performed from the intravenous catheter during operation. In all other spina
bifida-participants we will strive to obtain samples during vena punctures for
other clinical purposes. For the participants, there is no personal direct
benefit attached to cooperate with the study. The results of the study will
contribute to the knowledge and benefit for the whole spina bifida
patient-group.
The study is group related because a large number of the necessary patients for
this study are minors.