Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study

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Human Molecular Genetics Pages 805-812

Genome-wide scan for autism susceptibility genes
Introduction
Results
Discussion
Materials And Methods
   Families
   Genotyping
   Linkage analysis
Acknowledgements
References

Genome-wide scan for autism susceptibility genes

Anne Philippe^1,2,4, Maria Martinez³, Michel Guilloud-Bataille¹, Christopher Gillberg⁵, Maria Råstam⁵, Eili Sponheim⁺, Mary Coleman⁺, Michele Zappella⁺, Harald Aschauer+, Lionel Van Maldergem⁺, Christiane Penet², Josué Feingold¹, Alexis Brice², Marion Leboyer^1,4,* and the Paris Autism Research International Sibpair Study⁺

¹INSERM U155, Université Paris VII, 75005 Paris, France, ²INSERM U289, Hôpital de la Pitié-Salpétrière, 75013 Paris, France, ³INSERM U358, Hôpital Saint-Louis, 75010 Paris, France, ⁴Service de Psychopathologie de l'Enfant et l'Adolescent, Hôpital Robert Debré, 75019 Paris, France and ⁵Child Neuropsychiatry, Sahlgren University Hospital, S-413 45 Göteborg, Sweden Received November 17, 1998; Revised and Accepted February 19, 1999

Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominalP-values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).

INTRODUCTION

Autism (MIM 209850) is an aetiologically heterogeneous syndrome. Approximately 10-25% of autism cases are due to known medical conditions, involving environmental factors or genetic disorders (1,2). The cause remains unknown in the other cases. The risk of developing autism is ~50-100 times greater for siblings of autistic individuals than for the general population (3). Twin studies have shown a much higher concordance for monozygotic than for dizygotic twins, suggesting a strong genetic component to autism (4). Candidate gene studies with family-based case controls have demonstrated linkage disequilibrium between autism and a marker in the [gamma]-aminobutyric acid_A receptor subunit gene (GABRB3), and between autism and polymorphisms of the serotonin transporter gene (5-HTT) (5-7). The first genome-wide screen for autism, conducted by the International Molecular Genetic Study of Autism Consortium (IMGSAC), has suggested the involvement of six different chromosomal regions (4, 7, 10, 16, 19 and 22) (8). We undertook a full genome-wide screen for autism susceptibility loci, using the non-parametric sib-pair method in 51 multiplex families.

RESULTS

Fifty-one families (described in Table 1) including at least two siblings or half-siblings affected by autism were recruited. Full genotype information was available for all parents except four fathers. All the families were Caucasian, 18 were from Sweden (35%), 15 from France (29%), six from Norway (12%), five from the USA (10%), three from Italy (6%), two from Austria (4%) and two from Belgium (4%). The mean age of the probands was 13.5 years (4-44) and the sex ratio was 2.85 (77 boys and 27 girls). The non-verbal IQ distribution was: IQ >70 for 12.5% of the patients, between 50 and 70 for 30.5%, and <50 for 57%.

Table 1. Description of families

Number of families
Autosomal screening X chromosome screening

Two affected siblings 47 47

Two affected siblings: two half-siblings 0 2

Three affected siblings 1 1

Three affected siblings: two full and one half-sibling 1 1

Total number of affected sib-pairs 51 55

Sex of affected sib-pairs

Male/male 25 29

Male/female 22 22

Female/female 4 4

Table 2. Genome scan non-parametric linkage results: maximum lod score (MLS) values for two- or multipoint analyses (significance level [le]5%).

Locus Position (cM)^a Two-point analysis Multipoint analysis

MLS P-value MLS^b (% IBD sharing) P-value

D2S382 210.4 0.98 0.0160

PEAK 2 223.1 0.64 (62.7) 0.0659

D2S364 231.5 0.65 0.0400

PEAK 4 226.1 0.88 (61.0) 0.0352

D4S1535 226.1 0.92 0.0199

D5S417 0.0 0.75 0.0315

PEAK 5 0.0 0.84 (61.3) 0.0391

D6S283 128.0 1.02 0.0149

PEAK 6 132.8 2.23 (68.6) 0.0013

PEAK 7 135.3 0.83 (59.0) 0.0401

D7S486 135.3 0.52 0.0609

D10S217 196.9 0.61 0.0460

PEAK 10 212.0 0.84 (66.0) 0.0391

D15S128 0.0 0.66 0.0402

PEAK 15 41.1 1.10 (63.0) 0.0201

D15S118 41.1 0.76 0.0305

D16S3075 10.6 0.62 0.0456

PEAK 16 17.1 0.74 (60.5) 0.0506

D18S68 60.0 1.47 0.0046

PEAK 18 60.0 0.62 (58.5) 0.0695

D19S226 24.1 1.17 0.0102

PEAK 19 24.1 1.37 (61.9) 0.0103

DXS996 0.0 0.89 0.0210

PEAK X 0.0 0.40 (60.0) 0.0900

^aPosition, in cM (Haldane function), of loci from pter to qter. Marker frequencies were estimated from the data using the computer program ILINK from the Linkage software package (28). Inter-locus distances were estimated from the data using the VITESSE program (29).
^bMultipoint MLS values were maximized over the `possible triangle' (MAPMAKER/SIB version 2.1) except for X-marker data (ASPEX/sib-phase, version 1.14).

The results of two-point affected sib-pair analysis (SIBPAIR) are summarized in Table 2. A maximum lod score (MLS) >0.6 (nominal P < 0.05) was obtained for 12 of the 264 (4.5%) markers tested on chromosomes 2, 4, 5, 6, 10, 15, 16, 18, 19 and X. The highest two-point MLS values were for chromosomes 18 (D18S68, MLS = 1.47, P = 0.0046), 19 (D19S226, MLS = 1.17, P = 0.0102) and 6 (D6S283, MLS = 1.02, P = 0.0149).

Figure 1. Multipoint MLS values at each point location for each chromosome.

These potential regions were also significant at the 5% level in multipoint analysis except for those on chromosomes 2 (P = 0.0659), 18 (P = 0.0695) and X (P = 0.0900) (Fig. 1 and Table 2). Another potential susceptibility region was identified on chromosome 7 (MLS = 0.83, P = 0.0401). The most significant result was obtained for a region close to marker D6S283 (MLS = 2.23).

DISCUSSION

Our genome-wide scan revealed 11 chromosomal regions positively linked to autism with nominal P-values of 5% or lower. The multitests problem of these linkage analyses raises the challenging issue of what constitutes a statistically significant finding (9-11). It is also argued that to localize a gene and to replicate its localization require different criteria for significance (9,12). Nonetheless, there is agreement that replication studies are essential to distinguish true from false-positive linkage findings. Our study is, to our knowledge, the first replication study of the IMGSAC findings, the first genome-wide scan of autism (8). Using the genome-wide thresholds derived by Lander and Krugylak (9), none of our positive findings constitutes a `significant' linkage (i.e. P < 2.2 × 10^-5). In our independent sample of autism families, the number of markers significant at the 5% level is close to that expected by chance (13 out of 264). Although the statistical inference is weaker, some of our positive findings show, however, evidence consistent with excess sharing in regions reported by other candidate gene studies or by the IMGSAC group.

Four regions, on chromosomes 2q, 7q, 16p and 19p were identified that overlapped with those reported by the IMGSAC study. Two of these four regions gave the most significant scores in the IMGSAC study: chromosome regions 7q and 16p had peak MLS values of 3.55 and 1.97, respectively, in the English subgroup of 56 affected sib-pair families. However, for the total sample of 87 families, the evidence for linkage of autism to these regions was weaker (MLS = 2.53 and 1.51, respectively) (8). Interestingly, the proband of one affected sib-pair in our initial recruitment was excluded due to microduplication of 16p13. Another patient with autism and partial duplication of 16p has been reported (13). These data reinforce the hypothesis that a susceptibility locus for autism maps on chromosome 16p.

On the other hand, the present study did not replicate three positive results reported by IMGSAC. We found no evidence for excess of alleles shared identical by descent (IBD) on chromosomes 4p, 10p or 22p. There may be several reasons for these conflicting results: false-negative results due to our smaller sample size, false-positive results, genetic heterogeneity between data sets within or between studies, or differences in the diagnostic criteria used in the two studies. We evaluated the power of our family data set (given the observed family structures: sibship sizes, number of affected and unaffected sibs, and DNA availability) to detect an excess of marker alleles IBD sharing ( y) of 64 and 59%, corresponding to a locus-specific sibling recurrence risk ([lambda]s) of ~2 or 1.6, respectively. These are the values estimated in the total IMGSAC family data from the most significant findings, i.e. chromosomes 7q and 16p markers. Power estimates of our data set (rate of significant replicates out of 2000) were evaluated for different maximum MLS values (data not shown). Our family sample has good power to detect linkage when [lambda]s is [ge]2. Weaker genetic effects, as expected, are unlikely to be found. For instance, to replicate a finding at the 5% level, the power of our data set is 81 or 44% when y = 64 or 59%, respectively.

We also identified a potential susceptibility region, with positive results for three adjacent markers, on chromosome 15 (q11-q15). This region included the critical imprinted region for Prader-Willi and Angelman syndromes. Pericak-Vance et al. (14) reported weak linkage with autism for an overlapping region, in 15q11.2-q13, for a sample of 37 multiplex families. Cook et al. (5) demonstrated linkage disequilibrium between autism and the [gamma]-aminobutyric acid receptor subunit gene GABRB3, which maps to 15q11.2-q12. Several case reports have also described chromosomal abnormalities of the 15q11-q13 region associated with autistic features (15-17).

Finally, our study revealed six other regions potentially involved in autism on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. Excess of alleles shared IBD was most significant on chromosome 6q (MLS = 2.23, IBD = 68.6%). Based on estimated sharing probabilities (Z₀ = 0.157, Z₁ = 0.313, Z₂ = 0.107), the 6q-specific [lambda]s was 1.59. Interestingly, Cao et al. (18) provided evidence for a schizophrenia susceptibility locus on 6q13-q26 in independent data sets. Possible candidate genes in this region include those for myristoylated alanine-rich protein kinase C substrate (MACS), which may be involved in the development of the central nervous system, glutamate receptor 6 (GRIK6) and G protein-coupled receptor 6 (GPR6), which is most strongly expressed in the putamen.

Fine mapping of the regions identified is under way. Nevertheless, because of the large number of tests in genome-wide approaches, these findings require confirmation on other independent panels of families.

MATERIALS AND METHODS

Families

Families with at least two siblings or half-siblings fulfilling the DSM IV criteria for autistic disorder (19) and the Autism Diagnostic Interview (ADI) algorithm for ICD-10 childhood autism (20) were recruited for an international collaborative autism sib-pair project, involving seven countries (Austria, Belgium, France, Italy, Norway, Sweden and the USA). Subjects were included only after thorough clinical and medical examinations comprising a full exploration of medical and family history, physical (including meticulous skin examination involving Wood's light assessment), neuropsychological [appropriate IQ test or Vineland interview (21)] and neurological examination, standard karyotyping and fragile-X testing (either karyotype in folic acid-depleted medium or molecular genetic testing for the trinucleotide repeat expansion in the FMR-1 gene), brain imaging and blood and urine analysis. Cases diagnosed in which there were associated organic conditions, such as phenylketonuria, tuberous sclerosis, neurofibromatosis, hypomelanosis of Ito, Rett syndrome, Moebius syndrome, Duchenne muscular dystrophy, Down's syndrome, fragile X syndrome or other established chromosomal disorders, were excluded. However, severe mental retardation, epilepsy, mild motor co-ordination disorders, mild hearing deficits, attention deficits and tics were not exclusion criteria. Blood samples were taken from affected siblings and both parents. The study was approved by the ethical committees of the collaborating organizations. Informed consent forms were completed by the parents of each child included in the study.

Genotyping

Blood samples were collected from both parents and affected sib-pairs. DNA was extracted and lymphoblastoid cell lines generated. If one parent was unavailable, blood samples were also taken from unaffected siblings to increase the probability of inferring the genotype of the missing parent.

A complete genomic screen was performed with 252 autosomal and 12 X-linked microsatellite markers in the Gnthon Laboratory (Evry, France) (22). We used fluorescent primers. Polymerase chain reaction (PCR) was performed in a total volume of 50 µl, containing 80 ng of genomic DNA, 50 pmol of each primer, 0.125 mM dNTPs and 1 U Taq polymerase. The amplification buffer (1×) contained 10 mM Tris base pH 9, 50 mM KCl, 1.5 mM MgCl₂, 0.1% Triton X-100 and 0.01% gelatin. Reactions were performed using a hot-start procedure, with Taq polymerase added only after a first denaturation step of 5 min at 96°C. DNA was amplified in 35 cycles of denaturation (94°C for 40 s) and annealing (55°C for 30 s). An elongation step (72°C for 2 min) terminated the reaction after the last annealing. PCR products were combined into pools and typed using the semi-automated Genescan/Genotyper system on ABI 373A sequencing machines.

Linkage analysis

Non-parametric likelihood methods were used for linkage analysis. Pairwise linkage was conducted using the SIBPAIR program (23), which provides a likelihood-based test statistic for linkage. The likelihoods over all families are maximized as a function of the rate of marker alleles IBD ( y) among affected sibs, and the likelihood ratio test statistic T is calculated against the null hypothesis of y = 0.5 (T = 2Ln[L( y)/L( y = 0.5)]). The statistic follows a [chi]² distribution with 1 degree of freedom and can thus be expressed as a lod score, MLS = T/2ln(10). Multipoint affected sib-pair linkage analysis, which uses information from all markers simultaneously, was performed using the program MAPMAKER/SIBS (24) which tests linkage by the maximum likelihood ratio approach (25). At any chromosomal location, the likelihood of the observed marker information among affected sib-pairs is maximized as a function of the proportion of pairs sharing two, one and zero alleles IBD, and is compared, through a likelihood ratio test, with the likelihood of the marker data under the null hypothesis of no linkage (i.e. T = 2Ln[L(Z₂, Z₁, Z₀)/L(Z₂ = 0.25, Z₁ = 0.5, Z₀= 0.25)]). An evaluation of the [lambda]s attributed to a locus can be calculated as 0.25/Z₀ (24). Holmans has shown that the power of the test is increased when imposing constraints among Z parameters such as the possible triangle test (2Z₀ [le] Z₁ and Z₁ [le] 1/2) and that the resulting distribution of T is a mixture of [chi]²s with 1 and 2 degrees of freedom (26). The statistic can also be reported as a lod score: MLS = T/2ln(10). For X-chromosome marker data, the likelihood ratio test is a function of one parameter only (i.e. T = 2Ln[L(Z₁, 1 - Z₁)/L(Z₁= 0.5, Z₀= 0.5)]). The resulting distribution of T is a [chi]² distribution with 1 degree of freedom. Because the X chromosome version of MAPMAKER/SIBS program is not functional, multipoint MLS values for X marker data were computed using the sib-phase program of ASPEX package (25,27).

ACKNOWLEDGEMENTS

We would like to thank the subjects and their families for their co-operation with this study. We are grateful to Armelle Faure and Nathalie Chron for technical help in the Gnthon Laboratory, and to Jacky Bou, Yolaine Pothin and Agns Camuzat for technical assistance in the INSERM U289 laboratory. This work was supported by the Assistance Publique-Hopitaux-de-Paris (PHRC AOM95076 and CRC no. 932413), the Association Franaise contre les Myopathies, the Fondation France-Telecom, the Fondation Lilly and the Swedish Medical Research Council (grant no. K97-21X-11251-03CK). A.P. was funded by a grant from the Fondation pour la Recherche Médicale.

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*To whom correspondence should be addressed at INSERM U513, Hôpital Henri Mondor, 8 rue du Général Sarrail, 94010 Créteil, France. Tel: + 33 1 49 81 30 51; Fax: +33 1 49 81 30 59; Email: leboyer@ext.jussieu.fr
⁺Paris Autism Research International Sibpair Study:
Sweden. Child Neuropsychiatry, Sahlgren University Hospital, S-413 45 Gsteburg: Christopher Gillberg, Maria R[OElig]stam, Carina Gillberg and Agneta Nyden.
France. Consultation spcialise pour l'Autisme infantile, Hôpital Robert Debr, Paris: Marion Leboyer, Manuel Bouvard, Anne Philippe, Nadia Chabane and Marie-Christine Mouren-Simeoni; Service universitaire d'Explorations fonctionnelles et Neurophysiologie en Pdopsychiatrie, Hôpital Bretonneau, Tours: Catherine Barthlemy.
Norway. National Centers for Child Psychiatry and for Child Neurology, 0319 Oslo: Eili Sponheim, Ingrid Spurkland and Ola Skjeldal.
USA. George Washington School of Medicine, Washington, DC: Mary Coleman and Philip Pearl; Institute for Basic Research in Developmental Disabilities, Staten Island, New York: Ira Cohen and John Tsiouris.
Italy. Divisione di Neuropsichiatria Infantile, 53100 Siena: Michele Zappella, Grazia Menchetti and Alfonso Pompella.
Austria. UniversitStsklinik fYr Psychiatrie, Allgemeines Krankenhaus, A-1090 Vienna: Harald Aschauer.
Belgium. Institut de Pathologie et de Gnetique, 6280 Loverval: Lionel van Malldergerme.

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The Human Secretin Gene in Children With Autistic Spectrum Disorder: Screening for Polymorphisms and Mutations
J Child Neurol, August 1, 2005; 20(8): 701 - 704.
[Abstract] [PDF]

R. C. Samaco, A. Hogart, and J. M. LaSalle
Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3
Hum. Mol. Genet., February 15, 2005; 14(4): 483 - 492.
[Abstract] [Full Text] [PDF]

D. A. Schwartz, J. H. Freedman, and E. A. Linney
Environmental genomics: a key to understanding biology, pathophysiology and disease
Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R217 - R224.
[Abstract] [Full Text] [PDF]

B. Chih, S. K. Afridi, L. Clark, and P. Scheiffele
Disorder-associated mutations lead to functional inactivation of neuroligins
Hum. Mol. Genet., July 15, 2004; 13(14): 1471 - 1477.
[Abstract] [Full Text] [PDF]

L. T.-O. Lee, K.-C. Tan-Un, R. T.-K. Pang, D. T.-W. Lam, and B. K.-C. Chow
Regulation of the Human Secretin Gene Is Controlled by the Combined Effects of CpG Methylation, Sp1/Sp3 Ratio, and the E-Box Element
Mol. Endocrinol., July 1, 2004; 18(7): 1740 - 1755.
[Abstract] [Full Text] [PDF]

D. Castermans, V. Wilquet, J. Steyaert, W. van de Ven, J.-P. Fryns, and K. Devriendt
Chromosomal Anomalies in Individuals with Autism: A Strategy towards the Identification of Genes Involved in Autism
Autism, June 1, 2004; 8(2): 141 - 161.
[Abstract] [PDF]

F. J. Serajee, R. Nabi, Hailang Zhong, and A.H.M. Mahbubul Huq
Polymorphisms in Xenobiotic Metabolism Genes and Autism
J Child Neurol, June 1, 2004; 19(6): 413 - 417.
[Abstract] [PDF]

M S Yang, L Yu, T W Guo, S M Zhu, H J Liu, Y Y Shi, N-F Gu, G Y Feng, and L He
Evidence for association between single nucleotide polymorphisms in T complex protein 1 gene and schizophrenia in the Chinese Han population
J. Med. Genet., May 1, 2004; 41(5): e63 - e63.
[Full Text] [PDF]

R. Muhle, S. V. Trentacoste, and I. Rapin
The Genetics of Autism
Pediatrics, May 1, 2004; 113(5): e472 - e486.
[Abstract] [Full Text] [PDF]

F J Serajee, R Nabi, H Zhong, and A H M Mahbubul Huq
Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism
J. Med. Genet., November 1, 2003; 40(11): e119 - 119.
[Full Text] [PDF]

F J Serajee, H Zhong, R Nabi, and A H M M. Huq
The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism
J. Med. Genet., April 1, 2003; 40(4): e42 - 42.
[Full Text] [PDF]

H Zhong, F J Serajee, R Nabi, and A H M M. Huq
No association between the EN2 gene and autistic disorder
J. Med. Genet., January 1, 2003; 40(1): e4 - 4.
[Full Text] [PDF]

C. J. Newschaffer, D. Fallin, and N. L. Lee
Heritable and Nonheritable Risk Factors for Autism Spectrum Disorders
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[Full Text] [PDF]

Z Talebizadeh, D C Bittel, J H Miles, N Takahashi, C H Wang, N Kibiryeva, and M G Butler
No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD)
J. Med. Genet., November 1, 2002; 39(11): e70 - 70.
[Full Text] [PDF]

C-H Tsai, S L Graw, and L McGavran
8p23 duplication reconsidered: is it a true euchromatic variant with no clinical manifestation?
J. Med. Genet., October 1, 2002; 39(10): 769 - 774.
[Full Text] [PDF]

I Borg, M Squire, C Menzel, K Stout, D Morgan, L Willatt, P C M O'Brien, M A Ferguson-Smith, H H Ropers, N Tommerup, et al.
A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation
J. Med. Genet., June 1, 2002; 39(6): 391 - 399.
[Abstract] [Full Text] [PDF]

W.-H. Yung, P.-S. Leung, S. S. M. Ng, J. Zhang, S. C. Y. Chan, and B. K. C. Chow
Secretin Facilitates GABA Transmission in the Cerebellum
J. Neurosci., September 15, 2001; 21(18): 7063 - 7068.
[Abstract] [Full Text] [PDF]

P. J. ASHERSON and S. CURRAN
Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology
The British Journal of Psychiatry, August 1, 2001; 179(2): 122 - 128.
[Abstract] [Full Text] [PDF]

A. W. Sailer, H. Sano, Z. Zeng, T. P. McDonald, J. Pan, S.-S. Pong, S. D. Feighner, C. P. Tan, T. Fukami, H. Iwaasa, et al.
Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R
PNAS, June 7, 2001; (2001) 121170598.
[Abstract] [Full Text] [PDF]

E. Asano, H. Kuivaniemi, A.H.M. Mahbubul Huq, G. Tromp, M. Behen, R. Rothermel, J. Herron, and D. C. Chugani
A Study of Novel Polymorphisms in the Upstream Region of Vasoactive Intestinal Peptide Receptor Type 2 Gene in Autism
J Child Neurol, May 1, 2001; 16(5): 357 - 363.
[Abstract] [PDF]

L. Khare, G. D Strizheva, J. N Bailey, K.-S. Au, H. Northrup, M. Smith, S. L Smalley, and E. P. Henske
A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex
J. Med. Genet., May 1, 2001; 38(5): 347 - 349.
[Full Text]

International Molecular Genetic Study of Autism Co
Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q
Hum. Mol. Genet., April 1, 2001; 10(9): 973 - 982.
[Abstract] [Full Text] [PDF]

R. J. Daniels, J. F. Peden, C. Lloyd, S. W. Horsley, K. Clark, C. Tufarelli, L. Kearney, V. J. Buckle, N. A. Doggett, J. Flint, et al.
Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16
Hum. Mol. Genet., February 1, 2001; 10(4): 339 - 352.
[Abstract] [Full Text] [PDF]

M. Maziade, C. Merette, M. Cayer, M.-A. Roy, P. Szatmari, R. Cote, and J. Thivierge
Prolongation of Brainstem Auditory-Evoked Responses in Autistic Probands and Their Unaffected Relatives
Arch Gen Psychiatry, November 1, 2000; 57(11): 1077 - 1083.
[Abstract] [Full Text] [PDF]

J. A. Lamb, J. Moore, A. Bailey, and A. P. Monaco
Autism: recent molecular genetic advances
Hum. Mol. Genet., April 1, 2000; 9(6): 861 - 868.
[Abstract] [Full Text] [PDF]

A. W. Sailer, H. Sano, Z. Zeng, T. P. McDonald, J. Pan, S.-S. Pong, S. D. Feighner, C. P. Tan, T. Fukami, H. Iwaasa, et al.
Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R
PNAS, June 19, 2001; 98(13): 7564 - 7569.
[Abstract] [Full Text] [PDF]

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	Number of families Autosomal screening	X chromosome screening
Two affected siblings	47	47
Two affected siblings: two half-siblings	0	2
Three affected siblings	1	1
Three affected siblings: two full and one half-sibling	1	1
Total number of affected sib-pairs	51	55
Sex of affected sib-pairs
Male/male	25	29
Male/female	22	22
Female/female	4	4

Locus	Position (cM)^a	Two-point analysis		Multipoint analysis
Locus	Position (cM)^a	MLS	P-value	MLS^b (% IBD sharing)	P-value
D2S382	210.4	0.98	0.0160
PEAK 2	223.1			0.64 (62.7)	0.0659
D2S364	231.5	0.65	0.0400
PEAK 4	226.1			0.88 (61.0)	0.0352
D4S1535	226.1	0.92	0.0199
D5S417	0.0	0.75	0.0315
PEAK 5	0.0			0.84 (61.3)	0.0391
D6S283	128.0	1.02	0.0149
PEAK 6	132.8			2.23 (68.6)	0.0013
PEAK 7	135.3			0.83 (59.0)	0.0401
D7S486	135.3	0.52	0.0609
D10S217	196.9	0.61	0.0460
PEAK 10	212.0			0.84 (66.0)	0.0391
D15S128	0.0	0.66	0.0402
PEAK 15	41.1			1.10 (63.0)	0.0201
D15S118	41.1	0.76	0.0305
D16S3075	10.6	0.62	0.0456
PEAK 16	17.1			0.74 (60.5)	0.0506
D18S68	60.0	1.47	0.0046
PEAK 18	60.0			0.62 (58.5)	0.0695
D19S226	24.1	1.17	0.0102
PEAK 19	24.1			1.37 (61.9)	0.0103
DXS996	0.0	0.89	0.0210
PEAK X	0.0			0.40 (60.0)	0.0900

				A. I. Alvarez Retuerto, R. M. Cantor, J. G. Gleeson, A. Ustaszewska, W. S. Schackwitz, L. A. Pennacchio, and D. H. Geschwind Association of common variants in the Joubert syndrome gene (AHI1) with autism Hum. Mol. Genet., December 15, 2008; 17(24): 3887 - 3896. [Abstract] [Full Text] [PDF]

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				V. Wong Study of the Relationship Between Tuberous Sclerosis Complex and Autistic Disorder J Child Neurol, March 1, 2006; 21(3): 199 - 204. [Abstract] [PDF]

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				R. C. Samaco, A. Hogart, and J. M. LaSalle Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 Hum. Mol. Genet., February 15, 2005; 14(4): 483 - 492. [Abstract] [Full Text] [PDF]

				D. A. Schwartz, J. H. Freedman, and E. A. Linney Environmental genomics: a key to understanding biology, pathophysiology and disease Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R217 - R224. [Abstract] [Full Text] [PDF]

				B. Chih, S. K. Afridi, L. Clark, and P. Scheiffele Disorder-associated mutations lead to functional inactivation of neuroligins Hum. Mol. Genet., July 15, 2004; 13(14): 1471 - 1477. [Abstract] [Full Text] [PDF]

				L. T.-O. Lee, K.-C. Tan-Un, R. T.-K. Pang, D. T.-W. Lam, and B. K.-C. Chow Regulation of the Human Secretin Gene Is Controlled by the Combined Effects of CpG Methylation, Sp1/Sp3 Ratio, and the E-Box Element Mol. Endocrinol., July 1, 2004; 18(7): 1740 - 1755. [Abstract] [Full Text] [PDF]

				D. Castermans, V. Wilquet, J. Steyaert, W. van de Ven, J.-P. Fryns, and K. Devriendt Chromosomal Anomalies in Individuals with Autism: A Strategy towards the Identification of Genes Involved in Autism Autism, June 1, 2004; 8(2): 141 - 161. [Abstract] [PDF]

				F. J. Serajee, R. Nabi, Hailang Zhong, and A.H.M. Mahbubul Huq Polymorphisms in Xenobiotic Metabolism Genes and Autism J Child Neurol, June 1, 2004; 19(6): 413 - 417. [Abstract] [PDF]

				M S Yang, L Yu, T W Guo, S M Zhu, H J Liu, Y Y Shi, N-F Gu, G Y Feng, and L He Evidence for association between single nucleotide polymorphisms in T complex protein 1 gene and schizophrenia in the Chinese Han population J. Med. Genet., May 1, 2004; 41(5): e63 - e63. [Full Text] [PDF]

				R. Muhle, S. V. Trentacoste, and I. Rapin The Genetics of Autism Pediatrics, May 1, 2004; 113(5): e472 - e486. [Abstract] [Full Text] [PDF]

				F J Serajee, R Nabi, H Zhong, and A H M Mahbubul Huq Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism J. Med. Genet., November 1, 2003; 40(11): e119 - 119. [Full Text] [PDF]

				F J Serajee, H Zhong, R Nabi, and A H M M. Huq The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism J. Med. Genet., April 1, 2003; 40(4): e42 - 42. [Full Text] [PDF]

				H Zhong, F J Serajee, R Nabi, and A H M M. Huq No association between the EN2 gene and autistic disorder J. Med. Genet., January 1, 2003; 40(1): e4 - 4. [Full Text] [PDF]

				C. J. Newschaffer, D. Fallin, and N. L. Lee Heritable and Nonheritable Risk Factors for Autism Spectrum Disorders Epidemiol. Rev., December 1, 2002; 24(2): 137 - 153. [Full Text] [PDF]

				Z Talebizadeh, D C Bittel, J H Miles, N Takahashi, C H Wang, N Kibiryeva, and M G Butler No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD) J. Med. Genet., November 1, 2002; 39(11): e70 - 70. [Full Text] [PDF]

				C-H Tsai, S L Graw, and L McGavran 8p23 duplication reconsidered: is it a true euchromatic variant with no clinical manifestation? J. Med. Genet., October 1, 2002; 39(10): 769 - 774. [Full Text] [PDF]

				I Borg, M Squire, C Menzel, K Stout, D Morgan, L Willatt, P C M O'Brien, M A Ferguson-Smith, H H Ropers, N Tommerup, et al. A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation J. Med. Genet., June 1, 2002; 39(6): 391 - 399. [Abstract] [Full Text] [PDF]

				W.-H. Yung, P.-S. Leung, S. S. M. Ng, J. Zhang, S. C. Y. Chan, and B. K. C. Chow Secretin Facilitates GABA Transmission in the Cerebellum J. Neurosci., September 15, 2001; 21(18): 7063 - 7068. [Abstract] [Full Text] [PDF]

				P. J. ASHERSON and S. CURRAN Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology The British Journal of Psychiatry, August 1, 2001; 179(2): 122 - 128. [Abstract] [Full Text] [PDF]

				A. W. Sailer, H. Sano, Z. Zeng, T. P. McDonald, J. Pan, S.-S. Pong, S. D. Feighner, C. P. Tan, T. Fukami, H. Iwaasa, et al. Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R PNAS, June 7, 2001; (2001) 121170598. [Abstract] [Full Text] [PDF]

				E. Asano, H. Kuivaniemi, A.H.M. Mahbubul Huq, G. Tromp, M. Behen, R. Rothermel, J. Herron, and D. C. Chugani A Study of Novel Polymorphisms in the Upstream Region of Vasoactive Intestinal Peptide Receptor Type 2 Gene in Autism J Child Neurol, May 1, 2001; 16(5): 357 - 363. [Abstract] [PDF]