Genetics of primary headache disorders and associated syndromes

Primary headache disorders are at least partly determined by genetic factors.
Current treatment is not optimal and the burden of disease is large, both for
the individual patient and society. A better understanding of disease
pathophysiology is needed to identify novel treatment targets. The
identification of genes involved in primary headache disorders will help
pinpointing molecular pathways and profylactic treatment targets.

To evaluate to what extent primary headache disorders are caused by genetic
factors and to identify genes and pathways involved in the pathophysiology of
these disorders.

The genetic study designs applied can be divided into case-control studies and
family-based studies.

Overview of amendments and addenda
Research protocols:
- p133/99: Genetics of primary headache syndromes (1999); revised in 2012 as
P12.201
- p.07.079: Biochemical profiling of brain and cerebrospinal fluid in migraine
patients (2007)

Amendments/ addenda:
1. Title: Patient recruitment cluster headache
Content: Recruitment of cluster headache patients and their relatives for a
survey to describe the clinical spectrum of cluster headache
Function: Addendum to P12.201
Date: 18-02-2000

2. Title: Migraine website
Content: Patient recruitment for headache research through the project*s
website
Function: Addendum to p.07.079 and P12.201
Date: 13-12-2007, revised version submitted with P12.201

3. Title: Endothelial function in TREX1 mutation carriers 1.0
Content: Endothelial function tests in patients with RVCL and CADASIL
Function: Addendum to p.07.079 and P12.201
Date: 20-06-2008

4. Title: Endothelial function in TREX1 mutation carriers 2.0
Content: Extension of version 1.0 with capsaïcin test
Function: Extension of addendum #3 to p.07.079 and P12.201
Date: 04-05-2009

5. Title: Hypothalamic functioning in migraine; a diary study into the
premonitory and headache phases
Content: Diary study/ questionnaires to collect additional clinical
information from patients recruited via the headache research project*s
website
Function: Addendum to p.07.079 and P12.201
Date: 15-05-2009

6. Title: Recruitment of a control cohort for questionnaire studies and genetic
studies in the perspective of the LUMINA program
Content: Recruitment of controls for headache research through the project*s
website
Function: Addendum to p.07.079 and P12.201
Date: 14-03-2011

7. Title: Recruitment of ex-(pre-)eclampsia patients
Content: Recruitment of ex-(pre-)eclampsia patients for genetic research and
questionnaires via the headache research project*s website
i.c.w. UMCG
Function: Addendum to p.07.079 and P12.201
Date: 17-04-2012

8. Title: Gene expression profiling and epigenetics in patients with
primary headache disorders and associated syndromes
Content: Extension of the genetic studies described in P12.201 with a
buccal swab for DNA isolation, RNA isolation, measurement of
general blood markers to be used as a reference (e.g.
leukocyte count + differentiation) and biobanking of plasma and serum,
with the possibility to assess gene expression and
epigenetic markers not only cross-sectionally, but also in a follow-up design
(in
different disease states or with different environmental
factors). Only selected patient groups are invited for these additional
measurements, other participants still follow standard
procedures described in P12.201.
Function: Addendum to P12.201
Date: Submitted to METC LUMC in November 2013

9. Title: Biobanking at headache clinic
Content: From different patients group we will collect blood samples to
store in the LUMC Biobank. In the future, these samples can be used
for analyses of interest.
Function: Addendum to P12.201
Date: Submitted to METC LUMC in Oktober 2018

Case-control studies:
- Completion of at least two questionnaires, visit to a local laboratory for
blood withdrawal.

Family-based studies:
- Proband: completion of a questionnaire and an address list of relatives who
want to participate, drawing a pedigree of the family. House visit for direct
interview and obtaining DNA, or a telephone interview with blood withdrawal at
a local laboratory. If it is not possible to obtain a blood sample for DNA
isolation, a saliva kit is used instead.
- Other relatives: completion of a questionnaire. House visit for direct
interview and obtaining DNA, or a telephone interview with blood withdrawal at
a local laboratory. If it is not possible to obtain a blood sample for DNA
isolation, a saliva kit is used instead.
- Affected minors of any age, and unaffected minors between 12 and 18 years old
are included in these non-therapeutic family-based studies, because they
provide indispensable information for genetic studies that cannot be obtained
using non-related control subjects. In order to minimize the burden of
participation, information is also obtained from the parents and saliva kits
are preferred for minors aged <12 years.