A genetic study of left-handedness and language lateralization in extended pedigrees from a Dutch population isolate. An investigation of a possible endophenotype for psychosis

A possible solution to investigate genetic backgrounds of schizophrenia is the
use of mono, or oligogenic endophenotypes related to more fundamental aspects
of the disease. Decreased language lateralization, i.e. a more bilateral
pattern of cortical language representation has been associated with
schizophrenia. Decreased language lateralization is correlated to
left-handedness and both may serve as endophenotypes for schizophrenia. Both
can be studied rather effectively in 30 families from an isolated population in
large pedigrees regardless of the schizophrenia phenotype.

To perform a genetic study of left-handedness and language lateralization as
endophenotypes of schizophrenia. The study will make use of 30 extended
multigenerational pedigrees with multiple left-handers from Urk, an isolated
population in The Netherlands. Chromosomal candidate regions will be identified
by linkage analyses using left-handedness and language lateralization as
traits. Revealed regions may contain schizophrenia susceptibility genes.
Therefore, identified genomic areas or genes linked with left-handedness and/or
decreased lateralization will be tested for association in an existing sample
of more than 500 schizophrenia patients and a comparable healthy control group
from an earlier research project (00-035).

Patients visiting their doctor are screened using a validated handedness
questionnaire. Left-handed subjects with familial left-handedness will be
contacted. We aim to include 30 large families with three or more left-handed
subjects. Participation exists of three steps: 1) measurement of language
lateralization with functional Transcranial Doppler. This device measures
lateralization as a function of change in flow velocity in the right and left
medial cerebral arteries. During a paced letter fluency task language areas of
the dominant hemisphere will be activated to a higher degree than the
contralateral areas, inducing an asymmetrical increase in bloodflow in the
middle cerebral arteries. 2) subjects will participate in a Word production
test and a Modified test of Remote Association or Semantic Distance. 3) a small
blood sample (20ml) will be obtained for DNA extraction and genetic analysis.

Hereafter (co)segregation of handedness and language lateralization will be
determined, as well as a genome-wide linkage analysis using the highly
informative Linkage Mapping Set v2.5-MD10 of 400 microsatellite markers evenly
spaced at 10cM intervals throughout the human genome (Applied Biosystems).
Identified candidate genes or genomic regions will first be tested for
association with left-handedness in an existing sample of schizophrenia
patients with known handedness. When an association with left-handedness can be
replicated in the schizophrenia sample, the identified genes will be tested in
a case-control association design for their potential association with
schizophrenia.

fTCD is a non-invasive Doppler technique that has been used extensively and has
no known associated risks. People wear a headset to which the Doppler-probes
are attached. When wearing the headset causes distress it can easily be
adjusted or taken off. Bloodsamples from subjects will be taken by experienced
medical doctors, thus decreasing the risk of haematomas. Participation takes
only 60 minutes.