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Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder., Methods: The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 2017. DNA was obtained from dried blood spots collected at birth as part of routine screening. Polygenic risk scores (PRSs) for bipolar disorder, major depression, and schizophrenia were generated using a meta-PRS method combining internally and externally trained components. Associations between PRS and polarity at first episode, polarity at any episode, and number of episodes with a given polarity were evaluated for each disorder-specific PRS using logistic and negative binominal regressions adjusted for the other two PRSs, age, sex, genotype platform, and five ancestral principal components., Results: PRS for bipolar disorder was positively associated with any manic episodes (odds ratio=1.23, 95% CI=1.09-1.38). PRS for depression was positively associated with any depressive (odds ratio=1.11, 95% CI=1.01-1.23) and mixed (odds ratio=1.15, 95% CI=1.03-1.28) episodes and negatively associated with any manic episodes (odds ratio=0.76, 95% CI=0.69-0.84). PRS for schizophrenia was positively associated with any manic episodes (odds ratio=1.13, 95% CI=1.01-1.27), but only when psychotic symptoms were present (odds ratio for psychotic mania: 1.27, 95% CI=1.05-1.54; odds ratio for nonpsychotic mania: 1.06, 95% CI=0.93-1.20). These patterns were similar for first-episode polarity and for the number of episodes within each pole., Conclusions: PRSs for bipolar disorder, major depression, and schizophrenia are associated with episode polarity and psychotic symptoms in a congruent manner among individuals with bipolar disorder.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk., Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH., Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10 -8 ), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10 -6 ) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10 -7 ; rs73033497, p = 8.8 × 10 -7 ; rs7914279, p = 6.4 × 10 -7 ), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10 -7 ) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10 -7 ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10 -7 ) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05)., Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The authors investigated the associations between polygenic liability and progression to bipolar disorder or psychotic disorders among individuals diagnosed with unipolar depression in early life., Methods: A cohort comprising 16,949 individuals (69% female, 10-35 years old at the first depression diagnosis) from the iPSYCH Danish case-cohort study (iPSYCH2012) who were diagnosed with depression in Danish psychiatric hospitals from 1994 to 2016 was examined. Polygenic risk scores (PRSs) for major depression, bipolar disorder, and schizophrenia were generated using the most recent results from the Psychiatric Genomics Consortium. Hazard ratios for each disorder-specific PRS were estimated using Cox regressions with adjustment for the other two PRSs. Absolute risk of progression was estimated using the cumulative hazard., Results: Patients were followed for up to 21 years (median=7 years, interquartile range, 5-10 years). The absolute risks of progression to bipolar disorder and psychotic disorders were 7.3% and 13.8%, respectively. After mutual adjustment for the other PRSs, only the PRS for bipolar disorder predicted progression to bipolar disorder (adjusted hazard ratio for a one-standard-deviation increase in PRS=1.11, 95% CI=1.03, 1.21), and only the PRS for schizophrenia predicted progression to psychotic disorders (adjusted hazard ratio=1.10, 95% CI=1.04, 1.16). After adjusting for PRSs, parental history still strongly predicted progression to bipolar disorder (adjusted hazard ratio=5.02, 95% CI=3.53, 7.14) and psychotic disorders (adjusted hazard ratio=1.63, 95% CI=1.30, 2.06)., Conclusions: PRSs for bipolar disorder and schizophrenia are associated with risk for progression to bipolar disorder or psychotic disorders, respectively, among individuals diagnosed with depression; however, the effects are small compared with parental history, particularly for bipolar disorder.

Background: Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear., Aims: We used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder., Method: Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses., Results: PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder)., Conclusions: Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored., Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis., Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018., Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium., Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency)., Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002)., Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Background: Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.AimsTo test the prospective relationship of ADHD and anxiety with onset of bipolar disorder., Method: We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models., Results: Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12-2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98-27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47-27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83-87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66-41.40) compared with those with no prior ADHD or anxiety., Conclusions: Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.Declaration of interestNone.

Introduction: Childhood adversity is gaining increasing attention as a plausible etiological factor in the development of psychotic disorders. Childhood residential mobility is a potential risk factor that has received little attention in this context., Methods: We used registry data to estimate associations of residential mobility with narrow and broad schizophrenia and bipolar disorder across the course of childhood among 1.1 million individuals born in Denmark 1971-1991 and followed from age 15 through 2010. We assessed effect modification by sex, family history of mental disorder, the presence of siblings close in age, and distance moved., Results: In individual-year models adjusted for family history, urbanicity at birth, and parental age, mobility at all ages except the year of birth was associated with heightened risk of narrow and broad schizophrenia, and risk increased with age at moving and with the number of moves. Further adjustment for mobility at all ages 0-15 revealed associations mainly during the latter half of childhood, which were strongest during adolescence. Associations between mobility and bipolar disorder were fewer and weaker compared to schizophrenia. There was modest evidence of interaction with family history of psychiatric diagnosis, but little evidence for interaction by sex, the presence of closely-aged siblings, or distance moved. Schizophrenia associations did not appear attributable to increased mobility among adolescents with earlier onset., Conclusions: Mobility may increase risk for psychotic disorders, particularly schizophrenia. Children may be especially vulnerable during adolescence. Future research should investigate the importance of school changes and the potential for interaction with genetic risk., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia., Methods: To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method., Results: In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21)., Conclusions: There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A recent study published by our group implicated the bromodomain containing protein 1 (BRD1) gene located at chromosome 22q13.33 with schizophrenia (SZ) and bipolar affective disorder (BPD) susceptibility and provided evidence suggesting a possible role for BRD1 in neurodevelopment. The present study reports an association analysis of BRD1 and the neighboring gene ZBED4 using a Caucasian case-control sample from Denmark and England (UK/DK sample: 490 patients with BPD, 527 patients with SZ, and 601 control individuals), and genotypes obtained from a BPD genome wide association (GWA) study of an overlapping English sample comprising 506 patients with BPD and 510 control individuals (UCL sample). In the UK/DK sample we genotyped 11 SNPs in the BRD1 region, of which six showed association with SZ (minimal single marker P-values of 0.0014), including two SNPs that previously showed association in a Scottish population [Severinsen et al. (2006); Mol Psychiatry 11(12): 1126-1138]. Haplotype analysis revealed specific risk as well as protective haplotypes with a minimal P-value of 0.0027. None of the 11 SNPs showed association with BPD. However, analyzing seven BRD1 SNPs obtained from the BPD GWA study, positive associations with BPD was observed with all markers (minimal P-value of 0.0014). The associations reported add further support for the implication of BRD1 with SZ and BPD susceptibility., ((c) 2009 Wiley-Liss, Inc.)

Background: Seasonal spring peaks of suicide are highly replicated, but their origin is poorly understood. As the peak of suicide in spring could be a consequence of decompensation of mood disorders in spring, we hypothesized that prior history of mood disorders is predictively associated with suicide in spring., Methods: We analyzed the monthly rates of suicide based upon all 37,987 suicide cases in the Danish Cause of Death Registry from 1970 to 2001. History of mood disorder was obtained from the Danish Psychiatric Central Register and socioeconomical data from the Integrated Database for Labour Market Research. The monthly rate ratio of suicide relative to December was estimated using a Poisson regression. Seasonality of suicide between individuals with versus without hospitalization for mood disorders was compared using conditional logistic regression analyses with adjustment for income, marital status, place of residence, and method of suicide., Results: A statistically significant spring peak in suicide was observed in both groups. A history of mood disorders was associated with an increased risk of suicide in spring (for males: RR=1.18, 95% CI 1.07-1.31; for females: RR=1.20, 95% CI 1.10-1.32)., Limitations: History of axis II disorders was not analyzed. Danish socioeconomical realities have only limited generalizability., Conclusions: The results support the need to further investigate if exacerbation of mood disorders in spring triggers seasonal peaks of suicide. Identifying triggers for seasonal spring peaks in suicide may lead to uncovering novel risk factors and therapeutic targets for suicide prevention., (2009 Elsevier B.V. All rights reserved.)

Background: Previous studies have suggested that early parental death may be associated with the emergence of bipolar disorder in later life. However, it remains unknown whether this association applies specifically to parental death due to suicide or only to early parental death. The present study aimed to explore whether suicide as well as the non-suicidal death of father, mother, or siblings are associated with an increased risk for bipolar disorder, and whether the possible association is modified by the age at which the subject experiences such a death in the family., Methods: The subjects were born in 1960 or later and were first admitted to or had first contact with Danish psychiatric facilities between 1981 and 1998 with a diagnosis of bipolar disorder, and fifty age-matched controls per case were extracted. The effects of the deaths of relatives were estimated by means of a conditional logistic regression analysis., Results: Among 947 subjects with bipolar disorder and 47,350 controls, those having experienced the parental suicide were significantly associated with an increased risk for BPD (incidence rate ratios: 1.83 [95% confidence interval: 1.07 to 3.12] for paternal suicide, 3.44 [1.97 to 6.00] for maternal suicide), whereas the non-suicidal death of parents showed no such association. Those having experienced maternal suicide at some point before reaching 10 years of age were seven times as likely to develop bipolar disorder., Limitations: The cohort members were followed until, but not exceeding, the age of 38., Conclusion: Early parental, particularly maternal, suicide increases the risk for bipolar disorder in the offspring. Possible explanations include a family history of mental disorders as well as psychosocial factors.

Background: There are conflicting data regarding the socio-economic risk factors for bipolar disorders. The aim of the present study was to explore the association between the socio-economic status of an individual or the parent and the risk for bipolar disorder., Method: Two Danish registers were merged. From the data source, we extracted those born in 1960 or later, and those with a first-ever admission to, or contact with, Danish psychiatric facilities during 1981-1998 with a diagnosis of bipolar disorder. Fifty time-matched controls per case were chosen by the incidence-density sampling method. Effects of marital status, occupation, education, income, and wealth, of both subjects and the parents, were estimated using conditional logistic regression., Results: A total of 947 cases were matched to 47 350 controls. Those at high risk of bipolar disorders were: single subjects, those in receipt of social assistance, pension or sickness payments, unemployed, subjects with a shorter educational history, and subjects with lower income. Conversely, parental higher education and higher level of paternal wealth were associated with increased risk. These associations remained significant after adjustment for gender, family history of psychiatric diagnoses, and other socio-economic variables, and are unlikely to be explained by known biases., Conclusions: The associations of lower socio-economic indices of subjects may be explained as a consequence of the disease. The association of higher socio-economic indices of parents may be explained by socio-economic achievement in the family of origin.

Objective: There is a consensus that genetic factors are important in the causation of bipolar disorder (BPD); however, little is known about other risk factors in the aetiology of BPD. Our aim was to review the literature on such risk factors - risk factors other than family history of affective disorders - as predictors for the initial onset of BPD., Methods: We conducted a literature search using the MEDLINE, PsycINFO and EMBASE databases. We selected factors of interest including demographic factors, factors related to birth, personal, social and family backgrounds, and history of medical conditions. The relevant studies were extracted systematically according to a search protocol., Results: We identified approximately 100 studies that addressed the associations between antecedent environmental factors and a later risk for BPD. Suggestive findings have been provided regarding pregnancy and obstetric complications, winter-spring birth, stressful life events, traumatic brain injuries and multiple sclerosis. However, evidence is still inconclusive. Childbirth is likely to be a risk factor. The inconsistency across studies and methodological issues inherent in the study designs are also discussed., Conclusion: Owing to a paucity of studies and methodological issues, risk factors of BPD other than family history of affective disorders have generally been neither confirmed nor excluded. We call for further research.

• There was no significant association between the polygenic risk score (PRS) for bipolar disorder and not completing 9th grade at term. • Among randomly selected population controls, who completed the 9th grade at term, there was a statistically significant positive linear relationship between the PRS for bipolar disorder and exam grades in Danish (i.e., native language). • Among randomly selected population controls, who completed the 9th grade at term, having very low PRS for bipolar disorder was associated with obtaining exam grades below the average. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine the effect of prenatal exposure to severe life events on risk of affective disorders in the offspring. Methods: In a cohort of 1.1 million Danish births from May 1978 until December 1997, mothers were considered exposed if one (or more) of their close relatives died or was diagnosed with serious illness up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of affective disorder or 31 December 2007; hospital admissions were identified by linkage to the Central Psychiatric Register. Log-linear Poisson regression was used for data analysis. Results: The risk of affective disorders was increased in male offspring whose mothers were exposed to severe life events during the second trimester (adjusted RR 1.55 [95% CI 1.05–2.28]). There was an increased risk of male offspring affective disorders in relation to maternal exposure to death of a relative in the second trimester (adjusted RR 1.74 [95% CI 1.06–2.84]) or serious illness in a relative before pregnancy (adjusted RR 1.44 [95% CI 1.02–2.05]). There was no evidence for an association between prenatal exposure to severe life events and risk of female offspring affective disorders. Conclusions: Our population-based study suggests that prenatal maternal exposure to severe life events may increase the risk of affective disorders in male offspring. These findings are consistent with studies of populations exposed to famine and earthquake disasters which indicate that prenatal environment may influence the neurodevelopment of the unborn child. [Copyright &y& Elsevier]