Abstract
Gene–environment–development interactions are suggested to play a crucial role in psychiatric disorders. However, it is not clear if there are specific risk gene interactions with particular pre-, peri-, and postnatal risk factors for distinct disorders, such as adult attention-deficit-/hyperactivity disorder (aADHD) and bipolar disorder (BD). In this pilot study, the first aim was to investigate retrospective self-reports of pre-, peri-, and postnatal complications and risk factors from 126 participants (aADHD, BD, and healthy controls) and their mothers. The second aim was to investigate possible interaction between the previously published common risk gene variants of ADHD in the ADGRL3 (=LPHN3) gene (rs2305339, rs1397548, rs734644, rs1397547, rs2271338, rs6551665, and rs2345039) and shared risk gene variants of aADHD and BD in the DGKH gene (DGKH rs994856/rs9525580/rs9525584 GAT haplotype) and pre-, peri-, and postnatal risk factors in comparison to a healthy control group. After correction for multiple comparison, the following pre-, peri-, and postnatal risk factors remained statistically significant (p ≤ 0.0036) between healthy controls and ADHD and BD patients as one group: unplanned pregnancies, psychosocial stress of the mother during pregnancy, mode of delivery, shared decision-making regarding medical procedures during the delivery, perinatal bonding, number of crybabies, and quality of mother–child and father–child relationship. There were no significant environment–gene interactions. In our preliminary data, similar risk factors were found to be significantly associated with both disorders in comparison to healthy controls. However, larger and longitudinal studies and standardized and validated instruments to get a better understanding of the interaction of pre-, peri-, and postnatal complications and mental health in the offspring are needed.
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References
Arcos-Burgos M, Muenke M (2010) Toward a better understanding of ADHD. LPHN3 gene variants and the susceptibility to develop ADHD. Attent Deficit Hyperact Disord 2(3):139–147. https://doi.org/10.1007/s12402-010-0030-2
Banerjee TD, Middleton F, Faraone SV (2007) Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr (Oslo Norway, 1992) 96(9):1269–1274. https://doi.org/10.1111/j.1651-2227.2007.00430.x
Bauer M, Pfennig A (2005) Epidemiology of bipolar disorders. Epilepsia 46(Suppl 4):8–13
Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B et al (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13(2):197–207. https://doi.org/10.1038/sj.mp.4002012
Bernardi S, Cortese S, Solanto M, Hollander E, Pallanti S (2010) Bipolar disorder and comorbid attention deficit hyperactivity disorder. A distinct clinical phenotype? Clinical characteristics and temperamental traits. World J Biol Psychiatry 11(4):656–666. https://doi.org/10.3109/15622971003653238
Biederman J (2005) Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 57(11):1215–1220. https://doi.org/10.1016/j.biopsych.2004.10.020
Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248. https://doi.org/10.1016/S0140-6736(05)66915-2
Bielas H, Arck P, Bruenahl CA, Walitza S, Grunblatt E (2014) Prenatal stress increases the striatal and hippocampal expression of correlating c-FOS and serotonin transporters in murine offspring. Int J Dev Neurosci 38:30–35. https://doi.org/10.1016/j.ijdevneu.2014.07.006
Bruxel EM, Salatino-Oliveira A, Akutagava-Martins GC, Tovo-Rodrigues L, Genro JP, Zeni CP et al (2015) LPHN3 and attention-deficit/hyperactivity disorder. A susceptibility and pharmacogenetic study. Gene Brain Behav 14(5):419–427. https://doi.org/10.1111/gbb.12224
Choudhry Z, Sengupta SM, Grizenko N, Fortier M-E, Thakur GA, Bellingham J, Joober R (2012a) LPHN3 and attention-deficit/hyperactivity disorder. Interaction with maternal stress during pregnancy. J Child Psychol Psychiatry Allied Discip 53(8):892–902. https://doi.org/10.1111/j.1469-7610.2012.02551.x
Choudhry Z, Sengupta SM, Grizenko N, Fortier ME, Thakur GA, Bellingham J, Joober R (2012b) LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy. J Child Psychol Psychiatry 53(8):892–902. https://doi.org/10.1111/j.1469-7610.2012.02551.x
Chudal R, Sourander A, Polo-Kantola P, Hinkka-Yli-Salomaki S, Lehti V, Sucksdorff D et al (2014) Perinatal factors and the risk of bipolar disorder in Finland. J Affect Disord 155:75–80. https://doi.org/10.1016/j.jad.2013.10.026
Chudal R, Brown AS, Gissler M, Suominen A, Sourander A (2015) Is maternal smoking during pregnancy associated with bipolar disorder in offspring? J Affect Disord 171:132–136. https://doi.org/10.1016/j.jad.2014.09.030
Class QA, Abel KM, Khashan AS, Rickert ME, Dalman C, Larsson H et al (2014) Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress. Psychol Med 44(1):71–84. https://doi.org/10.1017/S0033291713000780
D’Onofrio BM, Class QA, Rickert ME, Larsson H, Langstrom N, Lichtenstein P (2013) Preterm birth and mortality and morbidity: a population-based quasi-experimental study. JAMA Psychiatry 70(11):1231–1240. https://doi.org/10.1001/jamapsychiatry.2013.2107
El Marroun H, Zeegers M, Steegers EAP, van der Ende J, Schenk JJ, Hofman A et al (2012) Post-term birth and the risk of behavioural and emotional problems in early childhood. Int J Epidemiol 41(3):773–781. https://doi.org/10.1093/ije/dys043
Faraone SV, Biederman J, Mennin D, Wozniak J, Spencer T (1997) Attention-deficit hyperactivity disorder with bipolar disorder: a familial subtype? J Am Acad Child Adolesc Psychiatry 36(10):1378–1387 (discussion 1387–1390)
Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry Off J World Psychiatr Assoc (WPA) 2(2):104–113
Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528–548. https://doi.org/10.1093/schbul/sbn187
Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CHD, Ramos-Quiroga JA et al (2012) The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 17(10):960–987. https://doi.org/10.1038/mp.2011.138
Gomez-Sanchez CI, Carballo JJ, Riveiro-Alvarez R, Soto-Insuga V, Rodrigo M, Mahillo-Fernandez I et al (2017) Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder. Long-term effects. Sci Rep 7(1):10391. https://doi.org/10.1038/s41598-017-10912-y
Halmøy A, Klungsøyr K, Skjærven R, Haavik J (2012) Preand perinatal risk factors in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 71(5):474–481. https://doi.org/10.1016/j.biopsych.2011.11.013
Harris MN, Voigt RG, Barbaresi WJ, Voge GA, Killian JM, Weaver AL, Colby CE, Carey WA, Katusic SK (2013) ADHD and learning disabilities in former late preterm infants: a population-based birth cohort. Pediatrics 132(3):e630–e636. https://doi.org/10.1542/peds.2012-3588
He C, Holme J, Anthony J (2014) SNP genotyping. The KASP assay. Methods Mole Biol (Clifton NJ) 1145:75–86. https://doi.org/10.1007/978-1-4939-0446-4_7
Kessler RC, Adler L, Barkley R, Biederman J, Conners C, Keith; Demler O et al (2006) The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 163(4):716–723. https://doi.org/10.1176/ajp.2006.163.4.716
Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J (2004) High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 161(10):1814–1821. https://doi.org/10.1176/ajp.161.10.1814
Klassen LJ (2010) Adult ADHD and its comorbidities, with a focus on bipolar disorder. J Affect Disord 124(1):1–8
Klassen LJ, Katzman MA, Chokka P (2010) Adult ADHD and its comorbidities, with a focus on bipolar disorder. J Affect Disord 124(1–2):1–8. https://doi.org/10.1016/j.jad.2009.06.036
Kleinhaus K, Harlap S, Perrin M, Manor O, Margalit-Calderon R, Opler M et al (2013) Prenatal stress and affective disorders in a population birth cohort. Bipolar Disord 15(1):92–99. https://doi.org/10.1111/bdi.12015
Langley K, Holmans PA, van den Bree BM, Thapar A (2007) Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of attention deficit hyperactivity disorder and associated antisocial behaviour: investigation in a clinical sample. BMC Psychiatry 7:26. https://doi.org/10.1186/1471-244X-7-26
Lesch KP, Merker S, Reif A, Novak M (2013) Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD. Eur Neuropsychopharmacol 23(6):479–491. https://doi.org/10.1016/j.euroneuro.2012.07.013
Li J, Olsen J, Vestergaard M, Obel C (2011) Low Apgar scores and risk of childhood attention deficit hyperactivity disorder. J Pediatr 158(5):775–779. https://doi.org/10.1016/j.jpeds.2010.10.041
Lindstrom K, Lindblad F, Hjern A (2011) Preterm birth and attention-deficit/hyperactivity disorder in schoolchildren. Pediatrics 127(5):858–865. https://doi.org/10.1542/peds.2010-1279
Lukkari S, Hakko H, Herva A, Pouta A, Riala K, Räsänen P (2012) Exposure to obstetric complications in relation to subsequent psychiatric disorders of adolescent inpatients. Specific focus on gender differences. Psychopathology 45(5):317–326. https://doi.org/10.1159/000336073
Lus G, Mukaddes NM (2009) Co-morbidity of bipolar disorder in children and adolescents with attention deficit/hyperactivity disorder (ADHD) in an outpatient Turkish sample. World J Biol Psychiatry 10(4 Pt 2):488–494. https://doi.org/10.1080/15622970902929876
Markham JA, Koenig JI (2011) Prenatal stress. Role in psychotic and depressive diseases. Psychopharmacology 214(1):89–106. https://doi.org/10.1007/s00213-010-2035-0
Martelon MaryKate, Wilens TE, Anderson JP, Morrison NR, Wozniak J (2012) Are obstetrical, perinatal, and infantile difficulties associated with pediatric bipolar disorder? Bipolar Disord 14(5):507–514. https://doi.org/10.1111/j.1399-5618.2012.01027.x
Martinez AF, Abe Yu, Hong S, Molyneux K, Yarnell D, Löhr H et al (2016) An ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility. Biol Psychiatry 80(12):943–954. https://doi.org/10.1016/j.biopsych.2016.06.026
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 60(5):497–502. https://doi.org/10.1001/archpsyc.60.5.497
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RMA, Petukhova M, Kessler RC (2007) Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64(5):543–552. https://doi.org/10.1001/archpsyc.64.5.543
Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S (2002) 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. https://doi.org/10.1097/00004583-200204000-00009
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
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215
Motlagh MG, Katsovich L, Thompson N, Lin H, Kim Y-S, Scahill L et al (2010) Severe psychosocial stress and heavy cigarette smoking during pregnancy: an examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome. Eur Child Adolescent Psychiatry 19(10):755–764. https://doi.org/10.1007/s00787-010-0115-7
Nigg JT, Breslau N (2007) Prenatal smoking exposure, low birth weight, and disruptive behavior disorders. J Am Acad Child Adolesc Psychiatry 46(3):362–369. https://doi.org/10.1097/01.chi.0000246054.76167.44
Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin, Li et al (2012) Preterm birth and psychiatric disorders in young adult life. Arch Gen Psychiatry 69(6):E1–E8. https://doi.org/10.1001/archgenpsychiatry.2011.1374
Owen D, Banjanin S, Gidrewicz D, McCabe L, Matthews SG (2005) Central regulation of the hypothalamic-pituitary-adrenal axis during fetal development in the Guinea-pig. J Neuroendocrinol 17(4):220–226. https://doi.org/10.1111/j.1365-2826.2005.01294.x
Park S, Kim B-N, Kim J-W, Shin M-S, Yoo HJ, Cho S-C (2017) Interactions between early trauma and catechol-O-methyltransferase genes on inhibitory deficits in children with ADHD. J Attent Disord 21(3):183–189. https://doi.org/10.1177/1087054714543650
Perricone G, Morales MR, Anzalone G (2013) Neurodevelopmental outcomes of moderately preterm birth: precursors of attention deficit hyperactivity disorder at preschool age. Spring Plus 2(1):221. https://doi.org/10.1186/2193-1801-2-221
Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA (2014) ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol 43(2):434–442. https://doi.org/10.1093/ije/dyt261
Pugliese V, Bruni A, Carbone EA, Calabrò G, Cerminara G, Sampogna G, Luciano M, Steardo L Jr, Fiorillo A, Garcia CS, De Fazio P (2018) Maternal stress, prenatal medical illnesses and obstetric complications: risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder. Psychiatry Res 271:23–30. https://doi.org/10.1016/j.psychres.2018.11.023
Quinn PD, Rickert ME, Weibull CE, Johansson ALV, Lichtenstein P, Almqvist C et al (2017) Association between maternal smoking during pregnancy and severe mental illness in offspring. JAMA Psychiatry 74(6):589–596. https://doi.org/10.1001/jamapsychiatry.2017.0456
Rodriguez A, Bohlin G (2005) Are maternal smoking and stress during pregnancy related to ADHD symptoms in children? J Child Psychol Psychiatry Allied Discip 46(3):246–254. https://doi.org/10.1111/j.1469-7610.2004.00359.x
Rutter M, Moffitt TE, Caspi A (2006) Gene-environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry Allied Discip 47(3–4):226–261. https://doi.org/10.1111/j.1469-7610.2005.01557.x
Sagiv SK, Epstein JN, Bellinger DC, Korrick SA (2013) Pre- and postnatal risk factors for ADHD in a nonclinical pediatric population. J Attent Disord 17(1):47–57. https://doi.org/10.1177/1087054711427563
Schenkel LS, West AE, Harral EM, Patel NB, Pavuluri MN (2008) Parent–child interactions in pediatric bipolar disorder. J Clin Psychol 64(4):422–437. https://doi.org/10.1002/jclp.20470
Schmitt A, Malchow B, Hasan A, Falkai P (2014) The impact of environmental factors in severe psychiatric disorders. Front Neurosci 8:19. https://doi.org/10.3389/fnins.2014.00019
Scott J, McNeill Y, Cavanagh J, Cannon M, Murray R (2006) Exposure to obstetric complications and subsequent development of bipolar disorder. Systematic review. Br J Psychiatry 189:3–11. https://doi.org/10.1192/bjp.bp.105.010579
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33;quiz 34–57
Silva D, Colvin L, Hagemann E, Bower C (2014) Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics 133(1):e14–e22. https://doi.org/10.1542/peds.2013-1434
Solberg BS, Halmoy A, Engeland A, Igland J, Haavik J, Klungsoyr K (2018) Gender differences in psychiatric comorbidity: a population-based study of 40 000 adults with attention deficit hyperactivity disorder. Acta Psychiatr Scand 137(3):176–186. https://doi.org/10.1111/acps.12845
Strang-Karlsson S, Raikkonen K, Pesonen A-K, Kajantie E, Paavonen E, Juulia; Lahti J et al (2008) Very low birth weight and behavioral symptoms of attention deficit hyperactivity disorder in young adulthood: the Helsinki study of very-low-birth-weight adults. Am J Psychiatry 165(10):1345–1353. https://doi.org/10.1176/appi.ajp.2008.08010085
Thapar A, Rice F, Hay D, Boivin J, Langley K, van den Bree M, Rutter M, Harold G (2009) Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design. Biol Psychiatry 66(8):722–727. https://doi.org/10.1016/j.biopsych.2009.05.032
van Hulzen KJ, Scholz CJ, Franke B, Ripke S, Klein M, McQuillin A, Sonuga-Barke EJ, Group PAW, Kelsoe JR, Landen M, Andreassen OA, Group PGCBDW, Lesch KP, Weber H, Faraone SV, Arias-Vasquez A, Reif A (2016) Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder: evidence from genome-wide association study meta-analysis. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2016.08.040
van den Bergh BRH, Marcoen A (2004) High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev 75(4):1085–1097. https://doi.org/10.1111/j.1467-8624.2004.00727.x
Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR et al (2018) Bipolar disorders. Nat Rev Dis Primers 4:18008. https://doi.org/10.1038/nrdp.2018.8
Wang LJ, Shyu YC, Yuan SS, Yang CJ, Yang KC, Lee TL, Lee SY (2016) Attention-deficit hyperactivity disorder, its pharmacotherapy, and the risk of developing bipolar disorder: a nationwide population-based study in Taiwan. J Psychiatr Res 72:6–14. https://doi.org/10.1016/j.jpsychires.2015.10.014
Weber H, Kittel-Schneider S, Gessner A, Domschke K, Neuner M, Jacob CP et al (2011) Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. Neuropsychopharmacology 36(10):2076–2085. https://doi.org/10.1038/npp.2011.98
Weinstock M (2005) The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav Immun 19(4):296–308. https://doi.org/10.1016/j.bbi.2004.09.006
Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32(6):1073–1086. https://doi.org/10.1016/j.neubiorev.2008.03.002
Zhu T, Gan J, Huang J, Li Y, Qu Y, Mu D (2016) Association between perinatal hypoxic-ischemic conditions and attention-deficit/hyperactivity disorder: a meta-analysis. J Child Neurol 31(10):1235–1244. https://doi.org/10.1177/0883073816650039
Zucchi FCR, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, Benzies K et al (2013) Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PLoS One 8(2):e56967. https://doi.org/10.1371/journal.pone.0056967
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We thank Theresia Töpner for the technical support and the patients and controls for participating in this study.
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SKS and AR received travel grants and authors’ honoraria from Shire and Medice. The other authors declared no conflicts of interest.
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Tole, F., Kopf, J., Schröter, K. et al. The role of pre-, peri-, and postnatal risk factors in bipolar disorder and adult ADHD. J Neural Transm 126, 1117–1126 (2019). https://doi.org/10.1007/s00702-019-01983-4
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DOI: https://doi.org/10.1007/s00702-019-01983-4