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Human Molecular Genetics Advance Access originally published online on November 17, 2004
Human Molecular Genetics 2005 14(1):171-178; doi:10.1093/hmg/ddi018
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13

Dalila Pinto1,4, Birgit Westland1, Gerrit-Jan de Haan2, Gabrielle Rudolf3, Berta Martins da Silva4, Edouard Hirsch3, Dick Lindhout1, Dorothée G.A. Kasteleijn-Nolst Trenité1,* and Bobby P.C. Koeleman1

1Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, 3508 AB, The Netherlands, 2Epilepsy Institute of The Netherlands SEIN, Heemstede, 2100 AA, The Netherlands, 3Clinique Neurologique, Hôpitaux Universitaires de Strasbourg, Strasbourg 67091, France and 4Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar, Porto 4099-003, Portugal

* To whom correspondence should be addressed at: DBG-Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands. Tel: +31 302504303; Fax: +31 302505301; Email: d.kasteleijn{at}dmg.azu.nl

Received September 20, 2004; Revised October 28, 2004; Accepted November 5, 2004


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 APPENDIX
 REFERENCES
 
Photoparoxysmal response (PPR) is an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. It is an epilepsy-related electroencephalographic trait with high prevalence in idiopathic epilepsies, especially in common idiopathic generalized epilepsies (IGEs), such as childhood absence epilepsy and juvenile myoclonic epilepsy. This degree of co-morbidity suggests that PPR may be involved in the predisposition to IGE. The identification of genes for PPR would, therefore, aid the dissection of the genetic basis of IGE. Sixteen PPR-multiplex families were collected to conduct a genome-wide linkage scan using broad (all PPR types) and narrow (exclusion of PPR types I and II and the occipital epilepsy cases) models of affectedness for PPR. We found an empirical genome-wide significance for parametric (HLOD) and non-parametric (NPL) linkage (Pgw(HLOD)=0.004 and Pgw(NPL)=0.01) for two respective chromosomal regions, 7q32 at D7S1804 (HLOD=3.47 with {alpha}=1, PNPL=3.39x10–5) and 16p13 at D16S3395 (HLOD=2.44 with {alpha}=1, PNPL=7.91x10–5). These two genomic regions contain genes that are important for the neuromodulation of cortical dynamics and may represent good targets for candidate-gene studies. Our study identified two susceptibility loci for PPR, which may be related to the underlying myoclonic epilepsy phenotype present in the families studied.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 APPENDIX
 REFERENCES
 
Photosensitivity or photoparoxysmal response (PPR) is a common epilepsy-related electroencephalographic (EEG) trait (reviewed in 1Go), defined as an abnormal cortical reaction of spike or spike-and-wave discharges triggered by intermittent photic stimulation (IPS). PPR responses range from occipital-spikes-only (OS) (or PPR type I) to generalized-spike-and-waves (GSWs) (or PPR types III and IV) (2Go), and have a prevalence of 1.4% in the general population of pediatric age (Kasteleijn-Nolst Trenité et al., personal communication). Seizures triggered by visual stimuli occur in up to 10% of epilepsies in childhood and in 5% of adult epilepsy patients (3Go). Modern visual scenes typically contain powerful seizure precipitants, such as the TV screen and videogames, raising the incidence of visually-sensitive epilepsies to a medical and social burden (4Go,5Go).

Since the late 1940s (6Go), family and twin studies have shown strong support for a genetic etiology for PPR. Case reports of monozygotic twins have shown an almost 100% concordance (7Go–10Go), and family studies have indicated a sibling recurrence risk of 20–30% that increased to 40% if one of the parents was also affected, and to ~50% when restricted to the 5–15 years age group examined (11Go–14Go). These heritability figures agree with the suggested autosomal dominant (AD) mode of inheritance with age-related reduced penetrance (7Go,9Go,12Go,15Go–17Go).

Despite increased interest in the genetics of photosensitivity and photosensitive epilepsies in recent years (13Go,18Go,19Go), and efforts to understand its syndromic associations (20Go–23Go), no genes have yet been identified. So far, it has only been suggested that chromosome 2 may harbor a PPR locus, based on a single report of a child, showing refractory myoclonic photosensitive epilepsy and a complex chromosomal rearrangement (24Go).

PPR is frequently associated with common idiopathic epilepsy syndromes, especially the idiopathic generalized epilepsies (IGEs). In fact, PPRs are found in up to 50% of IGE syndromes (1Go,21Go,25Go) in ~10–40% of subjects with myoclonic epilepsies of infancy, in 30–40% of subjects with juvenile myoclonic epilepsy (JME) and in 13–18% of subjects with absence epilepsies with childhood or juvenile-onset. Depending on the mode and intensity of the IPS, PPR may be evoked in up to 90% of JME subjects (26Go). In addition, PPR can also be observed in idiopathic partial epilepsies, such as benign occipital epilepsy with epileptiform discharges mainly restricted to the occipital area and visual aura resembling migraine (27Go).

The increased co-morbidity of PPR with the IGE compared with the general population suggests that PPR may be involved in the predisposition for IGE (11Go,28Go). To tackle the genetic complexity and heterogeneity characteristic of IGE (reviewed in 29Go,30Go), genome-wide scans have, so far, been conducted on families selected either on the proband's syndrome or on the family seizure type (31Go,32Go), although replication has often proven challenging (33Go–36Go). By focusing on epilepsy-related EEG patterns such as PPR, which can be evoked in the EEG laboratory independent of obvious clinical expression of the disease, a suitable endophenotype for finding loci involved in epileptogenesis may be provided. The identification of susceptibility loci for PPR will thus help in understanding the biological process of photosensitivity and may help in dissecting the complex genetic background of IGE.

Here, we present the first report of a genome-wide linkage scanning for an epilepsy-related EEG trait. We conducted a genome-wide scan for the PPR trait in 16 PPR-multiplex families with a prominent myoclonic epilepsy background. To further reduce possible heterogeneity, we performed linkage analysis taking into account broad and narrow models, restricting the phenotype to generalized PPR- and myoclonic epilepsy. Our results provide evidence for two PPR loci on chromosomes 7q32 and 16p13 that are likely to be related to the underlying epilepsy phenotype present in the family set studied.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 APPENDIX
 REFERENCES
 
Figure 1 shows the genomide-wide parametric linkage (HLOD, Fig. 1A) and non-parametric linkage (NPL) (PNPL, Fig. 1B) results. The corresponding chromosomal marker locations are shown in Figure 2.



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  		Figure 1. Genome-wide parametric linkage (A) and NPL (B) analysis for the broad and narrow phenotypes. Chromosomes are arranged in linear scale from pter to qter with cumulative distances given in centimorgans (cM, Haldane) (x-axis). HLOD scores and NPL-pointwise type-I-error rate (PNPL) are depicted on the y-axis. Empirically derived genome-wide P-value thresholds are indicated in the plots: broad model—HLOD score of 3.42 (A) and PNPL of 3x10–4 (B), with suggestive threshold levels of 1.93 and 2x10–3, respectively; narrow model—HLOD score of 2.8 (A) and PNPL of 2.45x10–4 (B), with suggestive level thresholds of 2.05 and 1.8x10–3, respectively.

 


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  		Figure 2. Chromosomes with genome-wide significance for linkage (genome-wide P-value < 0.05, (67Go). Empirically derived P-value thresholds are indicated for HLOD statistic (solid line) and PNPL statistic (dashed line). The x-axis indicates the markers used in the genome-wide scan, with genetic distances in cM. (A, B) The y-axis indicates the multipoint HLOD scores and PNPL values for chromosomes 7 (A) and 16 (B), respectively, assuming an AD mode of inheritance and a narrow phenotype.

 
For the broad model of affectedness, the maximum LOD score was found at 16p13 and peaked at D16S3395 (HLOD=2.44, {alpha}=1) (Fig. 1A). The corresponding non-parametric PNPL was 7.91x10–5, providing empirical genome-wide significance for linkage Pgw(NPL)=0.01 (Fig. 1B). The 1-LOD-unit confidence interval (CI) for the linkage peak was 0–13 cM in p telomere (pter). In addition, suggestive genome-wide evidence for linkage was obtained at 7q32 for both statistics (D7S1804, HLOD=2.04 with {alpha}=1, PNPL=9.79x10–4).

For the narrow model, the maximum LOD score was found at 7q32 at marker D7S1804 (HLOD of 3.47 with {alpha}=1 and PNPL=3.4x10–5) achieving significant genome-wide evidence for linkage (Fig. 2A). The likelihood of obtaining an HLOD score ≥3.47 by chance in a genome-wide scan was estimated to be 0.004 in 10 000 simulations. This HLOD score maintained significance (Pgw(HLOD)=0.008) even after conservatively accounting for the testing of two models of affectedness (broad and narrow). The 1-LOD-unit CI was 128–140 cM from pter. In addition, an HLOD of 2.35 ({alpha}=1) was obtained in the 16p13 region at D16S3395, coincident with the NPL evidence (Fig. 2B). The empirically derived probability of finding a PNPL ≤ 1.06x10–4 by chance in the whole genome was estimated to be 0.02.

Single-point parametric and non-parametric scores were in agreement with the multipoint linkage results (data not shown).

Taken together, analysis of the two phenotype models (broad and narrow) resulted in consistent peaks at 16p13 and 7q32, supported by both the parametric linkage (Fig. 1A) and the NPL analysis (Fig. 1B), and achieving empirical genome-wide significance (Pgw < 0.05). Finally, it should be noted that there was no evidence for heterogeneity among our families at these peaks as is indicated by the maximization of the LOD scores with {alpha}=1.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 APPENDIX
 REFERENCES
 
A phenotypic approach based on epilepsy-correlating biological markers, such as epilepsy-related EEG traits, rather than only the clinical expression, may facilitate the elucidation of the genetic predisposition involved in epilepsy disorders. Here, we applied this approach to the photosensitivity trait.

To identify susceptibility loci for photosensitivity, we conducted a genome-wide linkage scan for PPR in 16 multiplex families and identified linkage in two chromosomal regions 7q32 and 16p13, achieving empirical genome-wide significance for linkage.

Owing to its many syndromic associations (21Go), it is likely that variations in more than a single gene can cause photosensitivity, which may greatly depend on the epilepsy background of the families. However, the families that have been studied here have a relatively homogeneous myoclonic epilepsy (PPR–MS) background, not only among probands but also within families. In addition, we performed linkage analysis taking into account broad and narrow models of affectedness. Linkage analysis revealed evidence for a locus on 7q32 at D7S1804 with broad and narrow definitions of PPR, supported by both parametric and non-parametric analysis, and achieving empirical genome-wide evidence for linkage when the narrow model was considered (Pgw(HLOD)=0.004). This evidence was maintained after applying a conservative Bonferroni correction to account for the testing of broad and narrow models (Pgw(HLOD)=0.008). The increase in LOD score (from 2.04 to 3.47) for the narrow PPR definition suggests an increase in phenotypic homogeneity. It is known that generalized PPRs are mostly associated with IGEs (12Go,37Go–39Go). Therefore, when we used the narrow model, restricting the analysis to the generalized PPR types III and IV while excluding the idiopathic partial occipital lobe epilepsies, a selection for specific loci is expected, thus reflecting an increase in phenotypic homogeneity. Accordingly, it is likely that the locus on 7q32 confers susceptibility to PPR-generalized MS (PPR-GMS). Interestingly, a locus for spike-and-wave discharges in the GAERS rat model of IGE (locus Swd/gaers1) was mapped by homology to this region 7q31–34 (40Go). Recently, Porciatti et al. (41Go) pointed to a link between photosensitivity and altered cortical mechanisms of visual perception, and Parra et al. (42Go) proposed that changes in the normal synchronization of fast oscillations mediate the transition to PPR. This region harbors homologs of genes known to play a fundamental role in cortical synchronization and control of sensory input in rats, such as the genes encoding for the metabotropic glutamate receptor 8 (human: GRM8) (43Go–45Go) and the cholinergic-muscarinic type 2 acetylcholine receptor M2 (human: CHRM2) (46Go). The latter is known to be especially important during the transition from sleep to wakefulness (46Go). In addition, the distribution of myoclonic jerks, which occurs mainly on awakening, is attributed to a disturbance of the sleep-wake cycle (47Go,48Go). Taken together with the fact that PPR can be found in 90% of JME patients (26Go), GRM8 and CHRM2 are of interest as candidates for PPR-GMS.

In addition, we found a second locus on 16p13 at D16S3395 exceeding the threshold of empirical genome-wide significance for linkage in both models of affectedness (broad Pgw(NPL)=0.01, narrow Pgw(NPL)=0.02). These results suggest that rather than being restricted to a subset of families, the 16p13 locus is likely to have a more general role in the susceptibility for PPR. This region contains at least two genes potentially involved in epileptogenesis, the synaptogyrin III (SYNGR3) (49Go,50Go) and a sodium/hydrogen-exchanger (SLC9A3R2). The latter belongs to the same Na+/H+ exchanger (NHE) gene family, as the NHE1 gene known to be mutated in slow-wave epilepsy mutant mice (51Go).

In summary, our linkage study on PPR families, with a homogeneous underlying epilepsy phenotype and a consistent intra-familiar phenomenology, has proved to be a successful approach to map susceptibility loci for PPR. We were able to map two susceptibility loci, 7q32 and 16p13, in PPR families with a prominent myoclonic epilepsy background. These regions contain genes important in cortical dynamics, which represent promising candidates for mutation screening studies. Ideally, these loci will point towards key biological pathways and are thus important to our understanding of the biological process leading to photosensitivity.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
APPENDIX
 REFERENCES
 
Eligibility and recruitment of subjects
Sixteen PPR-multiplex families were recruited for this study. Medical ethical consent was obtained by each participating center and written informed consent was obtained from all participating patients and family members.

The inclusion criteria were: (i) a proband with PPR (types I–IV), with or without diagnosis of epilepsy or seizures and (ii) at least one more affected sibling or first-degree relative. Exclusion criteria were the presence of any abnormal neurological finding, such as trauma or morphological or metabolic disease.

Clinical and EEG data for each participant were documented in standardized anonymous protocols http://humgen.med.uu.nl/publications/pinto2004_2. Two epileptologists independently classified the epilepsy syndromes and assessed the EEG data and IPS reports in each recruiting epilepsy center. When clinical information and EEG data were inconclusive, the diagnosis was set as unknown. The IPS protocol allowed for the specification of PPR response into four types according to Waltz et al. (2Go) and allowed for the differentiation between unprovoked GSW discharges and GSW evoked by IPS, in agreement with the European guidelines (52Go). Accordingly, PPR was classified as type I (OS), type II (biphasic slow waves intermingled with spikes over the parieto-occipital area), type III (type II with generalization to the frontal regions) or type IV (GSW). Subjects without a proven PPR were set as unknown (affected-only approach) (18Go). Seizures and epileptic syndromes were diagnosed according to the revised ‘Classification of Epilepsies and Epileptic Syndromes of the International League Against Epilepsy’ (53Go,54Go).

Sample ascertainment and clinical characterization
Our sample consisted of 16 PPR-multiplex families with 105 members (49 affected, ~1 : 1.3 male/female). Fourteen multiplex Dutch families were ascertained over a period of 15 years through the outpatient clinic network of the Heemstede epilepsy centre (SEIN) and the Department of Medical Genetics of the University Medical Center Utrecht. Two multiplex French families were identified through the outpatient clinic of the Department of Neurology of the University Hospital of Strasbourg.

All probands except one had PPR type III or IV. The two PPR types III and IV were also the predominant type in the affected family members (47 PPR III and IV, 2 PPR II). All the probands also suffered from epilepsy, and 77% of the family members with PPRs also had epilepsy. Of the 16 PPR-families, 10 were ascertained through a proband with myoclonic seizures (five JME, two PSE-MS, three PSE-EM), one through a proband with eyelid myoclonia with absences, three through a proband with PSE-generalized tonic-clonic seizures and two through a proband with occipital epilepsy. None of the affected members had mental retardation or developmental problems. Detailed information about the pedigrees and syndromic classification of the affected members is available at http://humgen.med.uu.nl/publications/pinto2004_2.

IPS procedure
The IPS procedure followed the internationally accepted 1999 guidelines (luminance of the stimulator, distance to the lamp, three eye-conditions tested, i.e. eye-closure, eyes open and eyes closed, and frequencies up to 60 Hz during 5–10 s each) with determination of the photosensitivity ranges using lower and upper thresholds of flash frequencies evoking PPRs (55Go). Stimulation was carried out with a Grass PS 22 stimulator in a dimmed room using an unpatterned glass lamp with diffuser at a distance of 30 cm from the patient's eyes.

Models of affectedness
Family members were classified under two models of affectedness. In the broad model, family members with any PPR types I–IV (2Go) were considered affected. PPR patients with consistent focal asymmetry or slowing in EEG were set as unknown. All the other family members were classified as unknown. In the narrow model, only members with PPR types III and IV without occipital lobe epilepsy were classified as affected, thus focusing on the generalized PPRs. The diagnostic status of the remaining family members was set as unknown.

Genotyping
Blood samples were collected from 103 individuals available for the study. Genomic DNA was isolated from the white-cell fraction of the whole blood using a routine salting-out method. The samples were genotyped at the Department of Medical Genetics, University Medical Center Utrecht. Details of the PCR reaction and genotyping protocols are given on the supplementary website at http://humgen.med.uu.nl/publications/pinto2004_2. Details of the marker set used in the screen are available upon request. A total of 550 highly polymorphic microsatellite markers covering all 22 autosomes and the X chromosome were preferentially selected from the sex-average marker maps from Marshfield (56Go), spanning the genome at an average interval of ~8 cM with an average heterozygosity of ~0.78. We eliminated any gap ≥12 cM, and increased resolution (to better than 5 cM) and information content up to >80% in regions of interest. A region of interest was defined as a chromosomal region where three consecutive markers showed at least two suggestive statistics (PNPL < 0.05, Z>1.96 or LOD>1). Marker positions were verified using the deCODE map (57Go) and the human sequence assemblies from the National Center for Biotechnology Information (NCBI) build34, and marker maps were generated using a Perl script.

Quality control check
A stepwise quality control check was carried out prior to data analysis to avoid erroneous inferences about allele sharing, as follows: (i) assumed relationships between DNA samples were evaluated by GRR (58Go); (ii) Pedcheck (v 1.1) (59Go) was used to search for Mendelian inconsistencies and for putative errors in pedigree structure or sample switching, and independent re-typing was done to remove suspect genotypes; (iii) Mendelian-consistent genotypes identified as excessive and unlikely recombination events between closely linked markers were detected using the error-checking algorithm implemented in MERLIN (v 0.9.12b) (60Go), and the flagged genotypings (i.e. corresponding to a false-positive rate of P<0.02) were eliminated prior to analysis.

Linkage analysis
Linkage analysis was carried out by ALLEGRO (v 1.2c) (61Go). Parametric linkage analysis was performed assuming AD inheritance with reduced penetrance, according to previous studies (17Go), with the penetrance vectors set to 70%. Phenocopy rates of 0.04 and 0.005 were assumed for the broad and narrow models of affectedness, respectively. LOD scores were calculated allowing for heterogeneity (HLOD), which were maximized for different proportions ({alpha}) of linked families (62Go,63Go).

To avoid false-negative linkage results due to the selection of a wrong genetic model (64Go), NPL analysis was performed using the exponential NPL method (65Go).

Genome-wide plots were generated using Perl scripts and R-stat (v 1.8.1) (66Go).

Genome-wide statistical significance
Standard guidelines (67Go) were followed to establish appropriate genome-wide thresholds for suggestive and significant linkage for this particular dataset. We produced 10 000 replicates for each of the affection models by generation of random genotypes for every marker using the simulation option of MERLIN (v 0.9.12b) (60Go). MERLIN generates genotypes under the null hypothesis of linkage and conserves the number and frequency of alleles at each marker, the pattern of missing genotypes, the family structure and phenotype scores. Simulated genotypes were then analysed using ALLEGRO (v 1.2c) (61Go) in exactly the same manner in which we had analysed the real data. Empirical genome-wide significance (Pgw) was defined as the HLOD score or NPL P-value (PNPL) expected to occur by chance 0.05, 0.01 or 0.005 times ({alpha}) per genome-wide scan (67Go). Suggestive genome-wide level was established to be an HLOD score or PNPL expected to occur at least once in a genome-wide scan (67Go).


   ACKNOWLEDGEMENTS
 
The authors gratefully acknowledge all the patients and families who participated in this study and all the members of the clinical centers for their support. The authors acknowledge the help and valuable comments of Thomas Sander during the course of this work. The authors thank Adri Bader and Sandrien Slouwaar for their assistance in collecting the family material, Cisca Wijmenga for helpful comments and Jackie Senior for critically reviewing the manuscript. The authors acknowledge all the members of the European Consortium on the Genetics of Photosensitivity and Visually Sensitive Epilepsies; they are listed in the Appendix. This work was supported by grants from the Dutch Epilepsy Fund (95-04) and Genvlag (UMC Utrecht). D.P. was supported by the Portuguese Foundation for Science and Technology (MCT-FCT, grant SFRH/BD/1347/2000). D.P. spent 4 months in the Gene Mapping Centre, Max-Delbrück-Centrum, Berlin, Germany, during which she was partially supported by a Ter Meulen Foundation fellowship (TMF/DA/3397) from the Royal Netherlands Academy of Arts and Sciences (KNAW).


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 APPENDIX
REFERENCES
 
European consortium on Genetics of Photosensitivity and Visually Sensitive Epilepsies
Members of the consortium: Mario Brinciotti (Rome, Italy); Thanos Covanis (Athens, Greece); Colin Ferrie (London, UK); Mogens Laue Friis (Odense, Denmark); Pierre Genton (Marseille, France); Robert ten Houten (Alkmaar, the Netherlands); Lieven Lagae (Leuven, Belgium); Antonio Martins da Silva (Porto, Portugal); Bernd Neubauer (Giessen, Germany); Tom Panayiotopoulos (London, UK); Dominique Parain (Rouen, France); Jaime Parra (Heemstede, the Netherlands); Lucio Parmeggiani (Pisa, Italy); Birthe Pedersen (Aalborg, Denmark); Marta Piccioli (Rome, Italy); Guido Rubboli (Bologna, Italy); Ulrich Stephani (Kiel, Germany); Hans Stroink (Tilburg, the Netherlands); Pierre Szepetowski (Marseille, France); Carlo Alberto Tassinari (Bologna, Italy); Michel Veering (Alkmaar, the Netherlands); Frederico Vigevano (Rome, Italy); Stephan Waltz (Köln, Germany).

Electronic database information
URLs for data referred here are as follows:


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 APPENDIX
 REFERENCES
 

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