ADHD: Strategies to unravel its genetic architecture

Journal of Neural Transmission, Supplement

Volumn , Issue 69, 2005, Pages 1-17

  Buitelaar, J K ^a  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ATTENTION DEFICIT DISORDER; CHILD DEVELOPMENT; ENVIRONMENTAL FACTOR; GENETIC HETEROGENEITY; HEREDITY; HUMAN; MENTAL DISEASE; ONSET AGE; PHENOTYPE; PRIORITY JOURNAL; REVIEW;

ATTENTION DEFICIT DISORDER WITH HYPERACTIVITY; BEHAVIOR; CHILD; ENVIRONMENT; GENOME; HUMANS;

EID: 30344459443     PISSN: 03036995     EISSN: None     Source Type: Journal    
DOI: 10.1007/3-211-31222-6_1     Document Type: Review

References (99)

1. Alberts-Corush J, Firestone P, Goodman JT (1986) Attention and impulsivity characteristics of the biological and adoptive parents of hyperactive and normal control children. Am J Orthopsychiatry 56(3): 413-423
2. American Psychiatric Association (APA) (1994) Diagnostic and statistical manual of mental disorders, 4th edn (DSM-IV). APA, Washington DC
3. Anguelova M, Benkelfat C, Turecki G (2003a) A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. II. Suicidal behavior. Mol Psychiatry 8(7): 646-653
4. Anguelova M, Benkelfat C, Turecki G (2003b) A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. I. Affective disorders. Mol Psychiatry 8(6): 574-591
5. Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M (2004) Attention-deficit/ hyperactivity disorder in a population isolate: linkage to loci at 4q132 5q333 11q22 and 17p11. Am J Hum Genet 75(6): 998-1014
6. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65(3): 1157-1165
7. Asherson P (2004) Attention-Deficit Hyperactivity Disorder in the post-genomic era. Eur Child Adolesc Psychiatry 13 [Suppl 1]: 150-170
8. Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ, Slot RvR, Minderaa RB, Gunning WB, Pearson PL, Sinke RJ (2003) A whole-genome scan in 164 dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 72(5): 1251-1260
9. Banaschewski T, Roessner V, Dittmann RW, Santosh PJ, Rothenberger A (2004) Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc Psychiatry 13 [Suppl 1]: 102-116
10. Barkley RA, Fischer M, Edelbrock CS, Smallish L (1990) The adolescent outcome of hyperactive children diagnosed by research criteria. I. An 8-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 29(4): 546-557
11. Barr CL, Kroft J, Feng Y, Wigg K, Roberts W, Malone M, Ickowicz A, Schachar R, Tannock R, Kennedy JL (2002) The norepinephrine transporter gene and attention-deficit hyperactivity disorder. Am J Med Genet 114(3): 255-259
12. Bartels M, Van Den Oord EJ, Hudziak JJ, Rietveld MJ, van Beijsterveldt CE, Boomsma DI (2004) Genetic and environmental mechanisms underlying stability and change in problem behaviors at ages 3 7 10 and 12. Dev Psychol 40(5): 852-867
13. Biederman J, Newcorn J, Sprich S (1991) Comorbidity of attention deficit hyperactivity disorder with conduct depressive anxiety and other disorders. Am J Psychiatry 148: 564-577
14. Biederman J, Milberger S, Faraone SV, Kiely K, Guite J, Mick E, Ablon S, Warburton R, Reed E (1995) Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity. Arch Gen Psychiatry 52: 464-470
15. Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M (1997) Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry 36(2): 272-281
16. Botting N, Fowls A, Cooke RWI (1997) Attention Deficit Hyperactivity Disorders and other psychiatric outcomes in very low birth weight children at 12 years. J Child Psychol Psychiatry 38: 931-941
17. Breslau N, Brown GG, DelDotto JE, Kumar S, Ezhuthachan S, Andreski P, Hufnagle KG (1996) Psychiatric sequelae of low birth weight at 6 years of age. J Abnorm Child Psychol 24(3): 385-400
18. nd edn. Cambridge University Press, Cambridge, pp 30-63
19. Buitelaar JK, Rothenberger A (2004) Foreword - ADHD in the scientific and political context. Eur Child Adolesc Psychiatry 13 [Suppl 1]: 1-6
20. Buitelaar JK, Van der Gaag RJ, Swaab-Barneveld H, Kuiper M, Van Engeland H (1995) Prediction of clinical response to methylphenidate in children with attention-deficit hyperactivity disorder (abstract). Proc 10th ESCAP Congress 10: 92-93
21. Cantwell DP (1975) Genetics of hyperactivity. J Child Psychol Psychiatr Allied Disciplines 16(3): 261-264
22. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297: 851-854
23. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631): 386-389
24. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK (1996) The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 98(1): 91-101
25. Crosbie J, Schachar R (2001) Deficient inhibition as a marker for familial ADHD. Am J Psychiatry 158(11): 1884-1890
26. De Luca V, Muglia P, Vincent JB, Lanktree M, Jain U, Kennedy JL (2004) Adrenergic alpha 2C receptor genomic organization: association study in adult ADHD. Am J Med Genet B Neuropsychiatr Genet 127(1): 65-67
27. Demonet JF, Taylor MJ, Chaix Y (2004) Developmental dyslexia. Lancet 363(9419): 1451-1460
28. Durston S, Hulshoff Pol HE, Schnack HG, Buitelaar JK, Steenhuis MP, Minderaa RB, Kahn RS, Van Engeland H (2004) Magnetic resonance imaging of boys with attention-deficit/hyper-hyperactivity disorder and their unaffected siblings. J Am Acad Child Adolesc Psychiatry 43(3): 332-340
29. Durston S, Fossella JA, Casey BJ, Hulshoff Pol HE, Galvan A, Schnack HG, Steenhuis MP, Minderaa RB, Buitelaar JK, Kahn RS, Van Engeland H (2005) Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder their unaffected siblings and controls. Mol Psychiatry 10(7): 678-685
30. Faraone SV (2005a) The scientific foundation for understanding attention-deficit/hyperactivity disorder as a valid psychiatric disorder. Eur Child Adolesc Psychiatr 14(1): 1-10
31. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005b) Molecular genetics of attention deficit hyperactivity disorder. Biol Psychiatry 57(11): 1313-1323
32. Faraone SV, Biederman J (1994) Genetics of attention-deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 3: 285-302
33. Faraone SV, Doyle AE (2001) The nature and heritability of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 10(2): 299-316 viii-ix
34. Faraone SV, Biederman J, Monuteaux MC (2000) Toward guidelines for pedigree selection in genetic studies of Attention Deficit Hyperactivity Disorder. Genet Epidemiol 18: 1-16
35. Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, Macphie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del'Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL (2002) A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 70(5): 1183-1196
36. Fossati A, Novella L, Donati D, Donini M, Maffei C (2002) History of childhood attention deficit/hyperactivity disorder symptoms and borderline personality disorder: a controlled study. Compr Psychiatry 43(5): 369-377
37. Gillberg CL (1992) Autism and autistic-like conditions - subclasses among disorders of empathy. J Child Psychol Psychiat 33: 813-842
38. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF (2004) Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry 61(6): 618-627
39. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160(4): 636-645
40. Greene RW, Biederman J, Faraone SV, Ouellette CA, Penn C, Griffin SM (1996) Toward a new psychometric definition of social disability in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 35(5): 571-578
41. Handen BL, Johnson CR, Lubetsky MJ (2000) Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord 30: 245-255
42. Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N, Asherson P, Curran S, Gould A, Richards S, Lawson D, Pay H, Turic D, Langley K, Owen M, O'Donovan M, Thapar A, Fitzgerald M, Gill M (2002) Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatry 7(7): 718-725
43. Hille ET, den Ouden AL, Saigal S, Wolke D, Lambert M, Whitaker A, Pinto-Martin JA, Hoult L, Meyer R, Feldman JF, Verloove-Vanhorick SP, Paneth N (2001) Behavioural problems in children who weigh 1000g or less at birth in four countries. Lancet 357(9269): 1641-1643
44. Kadesjo B, Gillberg C, Hagberg B (1999) Brief report: autism and Asperger syndrome in seven-year-old children: a total population study. J Autism Dev Disord 29(4): 327-331
45. Kahn RS, Khoury J, Nichols WC, Lanphear BP (2003) Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive inattentive and oppositional behaviors. J Pediatr 143(1): 104-110
46. Larsson JO, Larsson H, Lichtenstein P (2004) Genetic and environmental contributions to stability and change of ADHD symptoms between 8 and 13 years of age: a longitudinal twin study. J Am Acad Child Adolesc Psychiatry 43(10): 1267-1275
47. Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J (1998) Psychiatric genetics: search for phenotypes. Trends Neurosci 21(3): 102-105
48. Levy F, Hay DA, McStephen M, Wood C, Waldman I (1997) Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry 36(6): 737-744
49. Loo SK, Fisher SE, Francks C, Ogdie MN, Macphie IL, Yang M, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL (2004) Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects. Mol Psychiatry 9(5): 485-493
50. Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ, Smith SD, Lee SY, Levy F, Kent L, Middle F, Rohde LA, Roman T, Tahir E, Yazgan Y, Asherson P, Mill J, Thapar A, Payton A, Todd RD, Stephens T, Ebstein RP, Manor I, Barr CL, Wigg KG, Sinke RJ, Buitelaar JK, Smalley SL, Nelson SF, Biederman J, Faraone SV, Gill M (2004) Joint analysis of the DRD5 marker concludes association with Attention-Deficit/Hyperactivity Disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet 74(2): 348-356
51. Luteijn E, Luteijn F, Jackson S, Volkmar F, Minderaa R (2000a) The children's Social Behavior Questionnaire for milder variants of PDD problems: evaluation of the psychometric characteristics. J Autism Dev Disord 30(4): 317-330
52. Luteijn EF, Serra M, Jackson S, Steenhuis MP, Althaus M, Volkmar F, Minderaa R (2000b) How unspecified are disorders of children with a pervasive developmental disorder not otherwise specified? A study of social problems in children with PDD-NOS and ADHD. Eur Child Adolesc Psychiatry 9(3): 168-179
53. Mannuzza S, Gittelman Klein R, Horowitz Konig P, Giampino TL (1989) Hyperactive boys almost grown up. IV. Criminality and its relationship to psychiatric status. Arch Gen Psychiatry 46: 1073-1079
54. Manor I, Corbex M, Eisenberg J, Gritsenkso I, Bachner-Melman R, Tyano S, Ebstein RP (2004) Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA). Am J Med Genet B Neuropsychiatr Genet 127(1): 73-77
55. Max JE, Lansing AE, Koele SL, Castillo CS, Bokura H, Schachar R, Collings N, Williams KE (2004) Attention deficit hyperactivity disorder in children and adolescents following traumatic brain injury. Dev Neuropsychol 25(1-2): 159-177
56. McEvoy B, Hawi Z, Fitzgerald M, Gill M (2002) No evidence of linkage or association between the norepinephrine transporter (NET) gene polymorphisms and ADHD in the Irish population. Am J Med Genet 114(6): 665-666
57. Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S (2002a) Case-control study of attention-deficit hyperactivity disorder and maternal smoking alcohol use and drug use during pregnancy. J Am Acad Child Adolesc Psychiatry 41(4): 378-385
58. Mick E, Biederman J, Prince J, Fischer MJ, Faraone SV (2002b) Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr 23(1): 16-22
59. Milberger S, Biederman J, Faraone SV, Chen L, Jones J (1996) Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? [see comments] Am J Psychiatry 153(9): 1138-1142
60. Milberger S, Biederman J, Faraone SV, Guite J, Tsuang MT (1997) Pregnancy delivery and infancy complications and attention deficit hyperactivity disorder: issues of gene-environment interaction. Biol Psychiatry 41(1): 65-75
61. Morrison JR, Stewart MA (1973) The psychiatric status of the legal families of adopted hyperactive children. Arch Gen Psychiatry 28(6): 888-891
62. Muhle R, Trentacoste SV, Rapin I (2004) The genetics of autism. Pediatrics 113(5): e472-486
63. Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C, Cantor RM, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL (2003) A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 72(5): 1268-1279
64. Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Bridge J, Greenhill L (1995) Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 25(3): 283-294
65. Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL (2003) The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry 8(1): 98-102
66. Rhee SH, Waldman ID, Hay DA, Levy F (1999) Sex differences in genetic and environmental influences on DSM-III-R attention-deficit/hyperactivity disorder. J Abnorm Psychol 108(1): 24-41
67. Risch N (1990a) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet 46(2): 229-241
68. Risch N (1990b) Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46(2): 222-228
69. Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405(6788): 847-856
70. Risch NJ, Zhang H (1996) Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations. Am J Hum Genet 58(4): 836-843
71. Robins E, Guze SB (1970) Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126(7): 983-987
72. Robinson WP, Wagstaff J, Bernasconi F, Baccichetti C, Artifoni L, Franzoni E, Suslak L, Shih LY, Aviv H, Schinzel AA (1993) Uniparental disomy explains the occurrence of the Angelman or Prader-Willi syndrome in patients with an additional small inv dup(15) chromosome. J Med Genet 30(9): 756-760
73. Rutter M, Maughan B, Meyer J, Pickles A, Silberg J, Simonoff E, Taylor E (1997) Heterogeneity of antisocial behavior: causes continuities and consequences. Nebr Symp Motiv 44: 45-118
74. Rutter ML, Kreppner JM, O'Connor TG (2001) Specificity and heterogeneity in children's responses to profound institutional privation. Br J Psychiatry 179: 97-103
75. Scahill L, Schwab-Stone ME, Merikangas KR, Leckman JF, Zhang H, Kasl S (1999) Psychosocial and clinical correlates of ADHD in a community sample of school-age children. J Am Acad Child Adolesc Psychiatry 38(8): 976-984
76. Schachar R, Levin HS, Max JE, Purvis K, Chen S (2004) Attention deficit hyperactivity disorder symptoms and response inhibition after closed head injury in children: do preinjury behavior and injury severity predict outcome? Dev Neuropsychol 25(1-2): 179-198
77. Seeger G, Schloss P, Schmidt MH, Ruter-Jungfleisch A, Henn FA (2004) Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism. Neurosci Lett 366(3): 282-286
78. Seidman LJ, Biederman J, Faraone SV, Milberger S, Norman D, Seiverd K, Benedict K, Guite J, Mick E, Kiely K (1995) Effects of family history and comorbidity on the neuropsychological performance of children with ADHD: preliminary findings. J Am Acad Child Adolesc Psychiatry 34(8): 1015-1024
79. Semrud-Clikeman M, Biederman J, Sprich-Buckminster S, Lehman BK, Faraone SV, Norman D (1992) Comorbidity between ADDH and learning disability: a review and report in a clinically referred sample. J Am Acad Child Adolesc Psychiatry 31(3): 439-448
80. Sherman DK, Iacono WG, McGue MK (1997) Attention-deficit hyperactivity disorder dimensions: a twin study of inattention and impulsivity-hyperactivity. J Am Acad Child Adolesc Psychiatry 36(6): 745-753
81. Silberg J, Rutter M, Meyer J, Maes H, Hewitt J, Simonoff E, Pickles A, Loeber R, Eaves L (1996) Genetic and environmental influences on the covariation between hyperactivity and conduct disturbance in juvenile twins. J Child Psychol Psychiatry 37(7): 803-816
82. Skuse DH (2001) Endophenotypes and child psychiatry. Br J Psychiatry 178: 395-396
83. Slaats-Willemse DIE, Swaab-Barneveld H, De Sonneville LMJ, van der Meulen EM, Buitelaar JK (2003) Deficient response inhibition as a cognitive endophenotype of ADHD. J Am Acad Child Adolesc Psychiatry 42: 1242-1248
84. Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ, McCracken JT, Macphie IL, Francks C, Fisher SE, Cantor RM, Monaco AP, Nelson SF (2002) Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13 in a region implicated in autism. Am J Hum Genet 71(4): 959-963
85. Sonuga-Barke EJ (2003) The dual pathway model of AD/HD: an elaboration of neurodevelopmental characteristics. Neurosci Biobehav Rev 27(7): 593-604
86. Sprich-Buckminster S, Biederman J, Milberger S, Faraone SV, Lehman BK (1993) Are perinatal complications relevant to the manifestation of ADD? Issues of comorbidity and familiality. J Am Acad Child Adolesc Psychiatry 32(5): 1032-1037
87. Taylor E, Sandberg S, Thorley G, Giles S (1991) The epidemiology of hyperactivity. Oxford University Press, Oxford
88. Thapar A, Holmes J, Poulton K, Harrington R (1999) Genetic basis of attention deficit and hyperactivity. Br J Psychiatry 174: 105-111
89. Thomson GOB, Raab GM, Hepburn WS, Hunter R, Fulton M, Laxen DPH (1989) Lood-lead levels and children's behavior: results from the Edinburgh lead study. J Child Psychol Psychiat 30: 515-528
90. Todd RD, Rasmussen ER, Neuman RJ, Reich W, Hudziak JJ, Bucholz KK, Madden PA, Heath A (2001) Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatry 158(11): 1891-1898
91. Todd RD, Rasmussen ER, Wood C, Levy F, Hay DA (2004) Should sluggish cognitive tempo symptoms be included in the diagnosis of attention-deficit/ hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 43(5): 588-597
92. Van Os J, Wichers M, Danckaerts M, Van Gestel S, Derom C, Vlietinck R (2001) A prospective twin study of birth weight discordance and child problem behavior. Biol Psychiatry 50(8): 593-599
93. Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358: 149-152
94. Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franceschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21(2): RC121
95. Weiss G, Hechtman L (1993) Hyperactive childen grown up ADHD in children adolescents and adults, 2nd ed. Guilford Press, New York
96. Whitaker AH, Van Rossum R, Feldman JF, Schonfeld IS, Pinto-Martin JA, Torre C, Shaffer D, Paneth N (1997) Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrassound abnormalities. Arch Gen Psychiatry 54: 847-856
97. Wilens TE (2004) Attention-deficit/hyperactivity disorder and the substance use disorders: the nature of the relationship subtypes at risk and treatment issues. Psychiatr Clin N Am 27(2): 283-301
98. Woodward L, Taylor E, Dowdney L (1998) The parenting and family functioning of children with hyperactivity. J Child Psychol Psychiatr Allied Disciplines 39(2): 161-169
99. Wright AF, Carothers AD, Pirastu M (1999) Population choice in mapping genes for complex diseases. Nat Genet 23(4): 397-404