ChIP-chip analysis of neurexins and other candidate genes for addiction and neuropsychiatric disorders

Journal of Neurogenetics

Volumn 24, Issue 1, 2010, Pages 5-17

  Pedrosa, Erika ^a   Kaushik, Sashank ^a   Lachman, Herbert M ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

Adhesion; Bipolar disorder; Chromatin immunoprecipitation; Dopamine; DRD2; Neurexin; Schizophrenia

Indexed keywords

NEUREXIN;

ADDICTION; ARTICLE; BRAIN; CHROMATIN IMMUNOPRECIPITATION; CONTROLLED STUDY; CTNNA3 GENE; DISEASE PREDISPOSITION; DRD2 GENE; FETUS; GABRA2 GENE; GABRG1 GENE; GENE; GENE MAPPING; GENE TARGETING; GENETIC VARIABILITY; HUMAN; HUMAN TISSUE; MENTAL DISEASE; NRXN1 GENE; NRXN3 GENE; OPRM1 GENE; PRIORITY JOURNAL; REGULATORY SEQUENCE; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 77149124247     PISSN: 01677063     EISSN: 15635260     Source Type: Journal    
DOI: 10.3109/01677060903305658     Document Type: Article

References (90)

1. Agrawal, V., Gupta, B., Banerjee, U. C., & Roy, N. (2008). A method for construction, cloning and expression of intronless gene from unannotated genomic DNA. Mol Biotechnol, 40(3), 217-223. [Epub 2008 Jun 10].
2. Alberini CM. (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol Rev, 89(1), 121-145.
3. Allemand, E., Batsche, E., & Muchardt, C. (2008). Splicing, transcription, and chromatin: a menage a trois. Curr Opin Genet Dev, 18(2), 145-151.
4. Atz, M. E., Rollins, B., & Vawter, M. P. (2007). NCAM1 association study of bipolar disorder and schizophrenia: polymorphisms and alternatively spliced isoforms lead to similarities and differences. Psychiatr Genet, 17(2), 55-67.
5. Bauer, L. O., Covault, J., Harel, O., Das, S., Gelernter, J., Anton, R., et al. (2007). Variation in GABRA2 predicts drinking behavior in project MATCH subjects. Alcohol Clin Exp Res, 31(11), 1780-1787.
6. Baum, A. E., Akula, N., Cabanero, M., Cardona, I., Corona, W., Klemens, B., et al. (2008). A genomewide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatr, 13(2), 197-207.
7. Bel-Vialar, S., Itasaki, N., Krumlauf, R. (2002). Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups. Development 129(22):5103-5115
8. Bernstein, B. E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D. K., Huebert, D. J., et al. (2005). Genomic maps and comparative analysis of histone modifi cations in human and mouse. Cell, 120(2), 169-181.
9. Berrettini, W., Yuan, X., Tozzi, F., Song, K., Francks, C., Chilcoat, H., et al. (2008). Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatr, 13(4), 368-373.
10. Bertram, L., Mullin, K., Parkinson, M., Hsiao, M., Moscarillo, T. J., Wagner, S. L., et al. (2007). Is alpha-T catenin (VR22) an Alzheimer's disease risk gene? J Med Genet, 44(1), e63.
11. Beuten, J., Ma, J. Z., Payne, T. J., Dupont, R. T., Crews, K. M., Somes, G., et al. (2005). Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are signifi cantly associated with nicotine dependence. Am J Hum Genet, 76(5), 859-864.
12. Bierut, L. J., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O. F., et al. (2007). Novel genes identifi ed in a high-density genomewide association study for nicotine dependence. Hum Mol Genet, 16(1), 24-35.
13. Bierut, L. J., Stitzel, J. A., Wang, J. C., Hinrichs, A. L., Grucza, R. A., Xuei, X., et al. (2008). Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatr, 165(9), 1163-1171.
14. Bond, C., LaForge, K. S., Tian, M., Melia, D., Zhang, S., Borg, L., et al. (1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A, 95(16), 9608-9613.
15. Conti, D. V., Lee, W., Li, D., Liu, J., Van Den Berg, D., Thomas, P. D., et al. (2008). Nicotinic acetylcholine receptor {beta}2 subunit gene implicated in a systems-based candidate gene study of smoking cessation. Hum Mol Genet, 17(18), 2834-2848.
16. Cooper, T. A. (2005). Use of minigene systems to dissect alternative splicing elements. Methods (San Diego, Calif.), 37(4), 331-340.
17. Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., & Kranzler, H. R. (2004). Allelic and haplotypic association of GABRA2 with alcohol dependence. Am J Med Genet Part B Neuropsychiatr Genet Int Soc Psychiatr Genet, 129(1), 104-109.
18. Covault, J., Gelernter, J., Jensen, K., Anton, R., & Kranzler, H. R. (2008). Markers in the 5'-region of GABRG1 associate with alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene. Neuropsychopharmacol Am Coll Neuropsychopharmacol, 33(4), 837-848.
19. Craig, A. M., & Kang, Y. (2007). Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol, 17(1), 43-52.
20. Dredge, B. K., & Darnell, R. B. (2003). Nova regulates GABA(A) receptor gamma 2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer. Mol Cell Biol, 23(13), 4687-4700.
21. Drgon, T., D'Addario, C., & Uhl, G. R. (2006). Linkage disequilibrium, haplotype, and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions. Am J Med Genet Part B Neuropsychiatr Genet Int Soc Psychiatr Genet, 141, 854-860.
22. Duan, J., Wainwright, M. S., Comeron, J. M., Saitou, N., Sanders, A. R., Gelernter, J., et al. (2003). Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet, 12(3), 205-216.
23. Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., et al. (2004). Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet, 74(4), 705-714.
24. Edenberg, H. J., & Foroud, T. (2006). The genetics of alcoholism: identifying specifi c genes through family studies. Addict Biol, 11(3-4), 386-396.
25. ENCODE Project Consortium, Birney, E., Stamatoyannopoulos, J. A., Dutta, A., Guigo, R., Gingeras, T. R., et al. (2007). Identifi cation and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 447(7146), 799-816.
26. Gelernter, J., Panhuysen, C., Weiss, R., Brady, K., Hesselbrock, V., Rounsaville, B., et al. (2005). Genomewide linkage scan for cocaine dependence and related traits: signifi cant linkages for a cocaine-related trait and cocaine-induced paranoia. Am J Med Genet Part B Neuropsychiatr Genet Int Soc Psychiatr Genet, 136B(1), 45-52.
27. Gelernter, J., Panhuysen, C., Wilcox, M., Hesselbrock, V., Rounsaville, B., Poling, J., et al. (2006). Genomewide linkage scan for opioid dependence and related traits. Am J Hum Genet, 78(5), 759-769.
28. Glatt, S. J., Lasky-Su, J. A., Zhu, S. C., Zhang, R., Zhang, B., Li, J., et al. (2008). Genomewide linkage analysis of heroin dependence in han chinese: results from wave two of a multistage study. Drug Alcohol Depend, 98(1-2), 30-34.
29. Graf, E. R., Zhang, X., Jin, S. X., Linhoff, M. W., & Craig, A. M. (2004). Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell, 119(7), 1013-1026.
30. Grucza, R. A., Wang, J. C., Stitzel, J. A., Hinrichs, A. L., Saccone, S. F., Saccone, N. L., et al. (2008). A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biolog Psychiatr, 64(11), 922-929.
31. Hashimoto, T., Arion, D., Unger, T., Maldonado-Aviles, J. G., Morris, H. M., Volk, D. W., et al. (2008). Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatr, 13(2), 147-161.
32. Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., et al. (2007). Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet, 39(3), 311-318.
33. Hernandez-Avila, C. A., Covault, J., Wand, G., Zhang, H., Gelernter, J., & Kranzler, H. R. (2007). Populationspecifi c effects of the Asn40Asp polymorphism at the muopioid receptor gene (OPRM1) on HPA-axis activation. Pharmacogenet Genom, 17(12), 1031-1038.
34. Hishimoto, A., Liu, Q. R., Drgon, T., Pletnikova, O., Walther, D., Zhu, X. G., et al. (2007). Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specifi c isoforms. Hum Mol Genet, 16(23), 2880-2891.
35. Hung, R. J., McKay, J. D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., et al. (2008). A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature, 452(7187), 633-637.
36. Ishiguro, H., Gong, J. P., Hall, F. S., Arinami, T., & Uhl, G. R. (2008). Association of PTPRB gene polymorphism with drug addiction. Am J Med Genet Part B Neuropsychiatr Genet, 147B(7), 1167-1172.
37. Ivaldi, M. S., Karam, C. S., & Corces, V. G. (2007). Phosphorylation of histone H3 at Ser10 facilitates RNA polymerase II release from promoter-proximal pausing in drosophila. Genes Dev, 21(21), 2818-2831.
38. Kang, Y., Zhang, X., Dobie, F., Wu, H., & Craig, A. M. (2008). Induction of GABAergic postsynaptic differentiation by {alpha}-neurexins. J Biolog Chem, 283(4), 2323-2334.
39. Keenan, I. D., Sharrard, R. M., & Isaacs, H. V. (2006). FGF signal transduction and the regulation of Cdx gene expression. Dev Biol, 299(2), 478-488.
40. Kfoury, N., & Kapatos, G. (2009). Identifi cation of neuronal target genes for CCAAT/enhancer binding proteins. Mol Cell Neurosci, 40(3), 313-327.
41. Kim, H. G., Kishikawa, S., Higgins, A. W., Seong, I. S., Donovan, D. J., Shen, Y., et al. (2008). Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet, 82(1), 199-207.
42. King, D. C., Taylor, J., Elnitski, L., Chiaromonte, F., Miller, W., & Hardison, R. C. (2005). Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences. Gen Res, 15(8), 1051-1060.
43. Kireeva, M. L., Hancock, B., Cremona, G. H., Walter, W., Studitsky, V. M., & Kashlev, M. (2005). Nature of the nucleosomal barrier to RNA polymerase II. Mol Cell, 18(1), 97-108.
44. Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M., et al. (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet, 17(3), 458-465.
45. Kolbe, D., Taylor, J., Elnitski, L., Eswara, P., Li, J., Miller, W., et al. (2004). Regulatory potential scores from genomewide three-way alignments of human, mouse, and rat. Gen Res, 14(4), 700-707.
46. Kornberg, R. D., & Lorch, Y. (1999). Chromatin-modifying and -remodeling complexes. Curr Opin Genet Dev, 9(2), 148-151.
47. Kreek, M. J., Nielsen, D. A., Butelman, E. R., & LaForge, K. S. (2005). Genetic infl uences on impulsivity, risk taking, stress responsivity, and vulnerability to drug abuse and addiction. Nat Neurosci, 8(11), 1450-1457.
48. Kwan, K.Y., Lam, M.M., Krsnik, Z., Kawasawa, Y.I., Lefebvre, V., Sestan, N. (2008). SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons. Proc Natl Acad Sci U S A. 105(41):16021-16026.
49. Lachman, H. M., Fann, C. S., Bartzis, M., Evgrafov, O. V., Rosenthal, R. N., Nunes, E. V., et al. (2007). Genomewide suggestive linkage of opioid dependence to chromosome 14q. HumMol Genet, 16(11), 1327-1334.
50. Li, M. D., Beuten, J., Ma, J. Z., Payne, T. J., Lou, X. Y., Garcia, V., et al. (2005). Ethnic- and gender-specifi c association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet, 14(9), 1211-1219.
51. Lian, H., Thompson, W. A., Thurman, R., Stamatoyannopoulos, J. A., Noble, W. S., & Lawrence, C. E. (2008). Automated mapping of large-scale chromatin structure in ENCODE. Bioinformatics (Oxford, England), 24(17), 1911-1916.
52. Lise, M. F., & El-Husseini, A. (2006). The neuroligin and neurexin families: from structure to function at the synapse. CMLS, 63(16), 1833-1849.
53. Liu, Q. R., Drgon, T., Johnson, C., Walther, D., Hess, J., & Uhl, G. R. (2006). Addiction molecular genetics: 639,401 SNP whole genome association identifi es many "cell adhesion" genes. Am J Med Genet Part B Neuropsychiatr Genet Int Soc Psychiatr Genet, 141(8), 918-925.
54. Liu, Q. R., Drgon, T., Walther, D., Johnson, C., Poleskaya, O., Hess, J., et al. (2005). Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples. Proc Natl Acad Sci U S A, 102(33), 11864-11869.
55. Luo X, Zhang X, Shao W, Yin Y, Zhou J. (2009). Crucial roles of MZF-1 in the transcriptional regulation of apomorphineinduced modulation of FGF-2 expression in astrocytic cultures. J Neurochem, 108(4), 952-961.
56. Mendenhall, E. M., & Bernstein, B. E. (2008). Chromatin state maps: new technologies, new insights. Curr Opin Genet Dev, 18(2), 109-115.
57. Miyashita, A., Arai, H., Asada, T., Imagawa, M., Matsubara, E., Shoji, M., et al. (2007). Genetic association of CTNNA3 with late-onset Alzheimer's disease in females. Hum Mol Genet, 16(23), 2854-2869.
58. Morgan, A. R., Hamilton, G., Turic, D., Jehu, L., Harold, D., Abraham, R., et al. (2008). Association analysis of 528 intragenic SNPs in a region of chromosome 10 linked to late-onset Alzheimer's disease. Am J Med Genet Part B Neuropsychiatr Genet, 147B(6), 727-731.
59. Need, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., et al. (2008). A genomewide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics, e1000373. Epub 2009 Feb 6.
60. Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., et al. (2007). Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a fl anking exonic splicing enhancer. Am J Hum Genet, 80(3), 416-432.
61. Nussbaum, J., Xu, Q., Payne, T. J., Ma, J. Z., Huang, W., Gelernter, J., et al. (2008). Signifi cant association of the neurexin 1 gene (NRXN1) with nicotine dependence in European and African-American smokers. Hum Mol Genet, 17(11), 1569-1577.
62. Oberley, M. J., Tsao, J., Yau, P., & Farnham, P. J. (2004). High-throughput screening of chromatin immunoprecipitates using CpG-island microarrays. Meth Enzymol, 376, 315-334.
63. O'Donovan, M.C., Norton, N., Williams, H., Peirce, T., Moskvina, V., Nikolov I., et al (2009): Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP fl anking fi broblast growth factor receptor 2. Mol Psychiatry 14:30-36.
64. Oslin, D. W., Berrettini, W., Kranzler, H. R., Pettinati, H., Gelernter, J., Volpicelli, J. R., et al. (2003). A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology Am Coll Neuropsychopharmacol, 28(8), 1546-1552.
65. Pedrosa, E., Stefanescu, R., Margolis, B., Petruolo, O., Lo, Y., Nolan, K., et al. (2008). Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia. Schizophr Res, 102(1-3), 210-219.
66. Pedrosa, E., Locker, J., Lachman, H. M. (2009). Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip) J Neurogenet, 18, 1-12.
67. Phillips, J. E., & Corces, V. G. (2009). CTCF: master weaver of the genome. Cell, 137(7), 1194-1211
68. Qu, H. Q., Lawrence, S. G., Guo, F., Majewski, J., & Polychronakos, C. (2006). Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms. BMC Genom, 7, 213.
69. Ray, L. A., & Hutchison, K. E. (2007). Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: a double-blind, placebo-controlled study. Arch Gen Psychiat, 64(9), 1069-1077.
70. Reich, T., Edenberg, H. J., Goate, A., Williams, J. T., Rice, J. P., Van Eerdewegh, P., et al. (1998). Genomewide search for genes affecting the risk for alcohol dependence. Am J Med Genet, 81(3), 207-215.
71. Robertson, A. G., Bilenky, M., Tam, A., Zhao, Y., Zeng, T., Thiessen, N., et al. (2008). Genomewide relation ship between histone H3 lysine 4 mono- and trimethylation and transcription factor binding. Gen Res, 18(12), 1906-1917
72. Roh, T. Y., Cuddapah, S., & Zhao, K. (2005). Active chromatin domains are defi ned by acetylation islands revealed by genome-wide mapping. Genes Dev, 19(5), 542-552.
73. Roh, T. Y., Wei, G., Farrell, C. M., & Zhao, K. (2007). Genomewide prediction of conserved and nonconserved enhancers by histone acetylation patterns. Gen Res, 17(1), 74-81.
74. Rowen, L., Young, J., Birditt, B., Kaur, A., Madan, A., Philipps, D. L., et al. (2002). Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity. Genomics, 79(4), 587-597.
75. Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P., Barnes, M. R., Toulopoulou, T., et al. (2008). Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet, 18(5), 988-996.
76. Schubert, L. A., Jeffery, E., Zhang, Y., Ramsdell, F., & Ziegler, S. F. (2001). Scurfi n (FOXP3) acts as a repressor of transcription and regulates T-cell activation. J Biolog Chem, 276(40), 37672-37679.
77. Shimizu, T., Bae, Y. K., & Hibi, M. (2006). Cdx-Hox code controls competence for responding to Fgfs and retinoic acid in zebrafi sh neural tissue. Development, 133(23), 4709-4719.
78. Soyka, M., Preuss, U. W., Hesselbrock, V., Zill, P., Koller, G., & Bondy, B. (2008). GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res, 42(3), 184-191.
79. Taylor, J., Tyekucheva, S., King, D. C., Hardison, R. C., Miller, W., & Chiaromonte, F. (2006). ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. Gen Res, 16(12), 1596-1604.
80. Terwisscha van Scheltinga, A. F., Bakker, S. C., & Kahn, R. S. (2009). Fibroblast growth factors in schizophrenia. Schizophr Bull, May 8. [Epub ahead of print].
81. Thomas, D. J., Rosenbloom, K. R., Clawson, H., Hinrichs, A. S., Trumbower, H., Raney, B. J., et al. (2007). The ENCODE project at UC Santa Cruz. Nucl Acids Res, 35(Database issue), D663-D667.
82. Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., et al. (2008). A variant associated with nicotine dependence, lung cancer, and peripheral arterial disease. Nature, 452(7187), 638-642.
83. Ushkaryov, Y. A., & Sudhof, T. C. (1993). Neurexin III alpha: extensive alternative splicing generates membrane-bound and soluble forms. Proc Natl Acad Sci U S A, 90(14), 6410-6414.
84. Vrijenhoek, T., Buizer-Voskamp, J.E., van der Stelt, I., Strengman, E., Sabatti, C., Geurts van Kessel, A., et al. (2008). Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet, 83(4), 504-510.
85. Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., et al. (2008). Rare structural variants disrupt multiple genes in deurodevelopmental pathways in schizophrenia. Science, 320(5875), 539-543.
86. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature, 459, 528-533.
87. Xie, G.X., Han, X., Ito, E., Yanagisawa, Y., Maruyama, K., Sugano, S., et al. (2003). Gene structure, dual-promoters, and mRNA alternative splicing of the human and mouse regulator of G-protein signaling GAIP/RGS19. J Mol Biol, 325(4), 721-732.
88. Xu, X., Bieda, M., Jin, V. X., Rabinovich, A., Oberley, M. J., Green, R., et al. (2007). A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members. Gen Res, 17(11), 1550-1561.
89. Yan, J., Noltner, K., Feng, J., Li, W., Schroer, R., Skinner, C., et al. (2008). Neurexin 1 alpha structural variants associated with autism. Neurosci Lett, 438(3), 368-370.
90. Yang, B. Z., Kranzler, H. R., Zhao, H., Gruen, J. R., Luo, X., & Gelernter, J. (2007). Association of haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 to alcohol dependence in independent case control and family samples. Hum Mol Genet, 16(23), 2844-2853.