Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Mehta, Divya; Tropf, Felix C.; Gratten, Jacob; Bakshi, Andrew; Zhu, Zhihong; Bacanu, Silviu‐Alin; Hemani, Gibran; Magnusson, Patrik K. E.; Barban, Nicola; Esko, Tõnu; Metspalu, Andres; Snieder, Harold; Mowry, Bryan; Kendler, Kenneth S.; Yang, Jian; Visscher, Peter M.; McGrath, John J.; Mills, Melinda; Wray, Naomi R.; Lee, Sang; Andreassen, Ole A.; Bramon, Elvira; Bruggeman, Richard; Buxbaum, Joseph D.; Cairns, Murray J.; Cantor, Rita M.; Cloninger, C. Robert; Cohen, David; Crespo‐Facorro, Benedicto; Darvasi, Ariel; DeLisi, Lynn E.; Dinan, Timothy G.; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Escott‐Price, Valentina; Freimer, Nelson B.; Georgieva, Lyudmila; Haan, Lieuwe de; Henskens, Frans; Joa, Inge; Juliá, Antonio; Khrunin, Andrey; Lerer, Bernard; Limborska, Svetlana A.; Loughland, Carmel M.; Maçek, Milan; Marsal, Sara; McCarley, Robert W.; McIntosh, Andrew M.; McQuillin, Andrew; Melegh, Béla; Michie, Patricia T.; Morris, Derek W.; Murphy, Kieran C.; Myin-Germeys, Inez; Olincy, Ann; Os, Jim van; Pantelis, Christos; Posthuma, Daniëlle; Quested, Digby; Schall, Ulrich; Scott, Rodney J.; Seidman, Larry J.; Тончева, Драга; Tooney, Paul A.; Waddington, John L.; Weinberger, Daniel R.; Weiser, Mark; Wu, Jing Qin

doi:10.1001/jamapsychiatry.2016.0129

Cited by 54 publications

(73 citation statements)

References 32 publications

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“…Potentially causal genes for the associations identified by GWAS were identified using four previously described bioinformatics tools: ToppGene 4 , Endeavour 5 , MetaRanker 6 , and DEPICT 7 . To this end, we first retrieved positional coordinates for all lead SNPs according to GRCh37/hg19 using Ensembl’s BioMart.…”

Section: Methodsmentioning

confidence: 99%

“…Human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has been associated with human development, 1,2 infertility 3,4 and neuropsychiatric disorders 5 . Reproductive tempo (AFB) and quantum (NEB) are cross-cutting topics in the medical, biological, evolutionary and social sciences and central in national and international policies.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Barban¹,

Jansen²,

Vlaming³

et al. 2016

Nat Genet

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The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Barban¹,

Jansen²,

Vlaming³

et al. 2016

Nat Genet

Self Cite

310

265

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show abstract

“…In addition to the epidemiological evidence for a relationship between female reproductive traits and psychiatric disorder risk in offspring, studies have found a genetic basis for reproductive behavior traits 21,22 and psychiatric disorders [23][24][25] .…”

Section: Introductionmentioning

confidence: 99%

“…A few studies focused on understanding the complex genetic relationship between reproductive traits and psychiatric disorders 32 . For instance, recent studies have revealed genetic overlap between the risk of SCZ and AFB 23,25 . They showed a U-shaped relationship between AFB and the polygenic risk score of SCZ 23 , demonstrating that the epidemiological observation of a (phenotypic) association between maternal age and SCZ risk in offspring (e.g.…”

Section: Introductionmentioning

confidence: 99%

The genetic relationship between female reproductive traits and six psychiatric disorders

Amare

Zhou

et al. 2018

Preprint

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Female reproductive behaviors have an important implication in evolutionary fitness and health of offspring. Previous studies have shown that age at first birth of women (AFB) is genetically associated with schizophrenia (SCZ). However, for most other psychiatric disorders and reproductive traits, the latent shared genetic architecture is largely unknown. Here we used the second wave of UK Biobank data (N=220,685) to evaluate the association between five female reproductive traits and polygenetic risk scores (PRS) projected from genome-wide association study summary statistics of six psychiatric disorders (N=429,178). We found that the PRS of attentiondeficit/hyperactivity disorder (ADHD) were strongly associated with AFB (genetic correlation of -0.68 ± 0.03 with p-value = 1.86E-89), age at first sexual intercourse (AFS) (-0.56 ± 0.03 with p-value = 3.42E-60), number of live births (NLB) (0.36 ± 0.04 with p-value = 4.01E-17) and age at menopause (-0.27 ± 0.04 with p-value = 5.71E-13). There were also robustly significant associations between the PRS of eating disorder (ED) and AFB (genetic correlation of 0.35 ± 0.06), ED and AFS (0.19 ± 0.06), Major depressive disorder (MDD) and AFB (-0.27 ± 0.07), MDD and AFS (-0.27 ± 0.03) and SCZ and AFS (-0.10 ± 0.03). Our findings reveal the shared genetic architecture between the five reproductive traits in women and six psychiatric disorders, which have a potential implication that helps to improve reproductive health in women, hence better child outcomes. Our findings may also explain, at least in part, an evolutionary hypothesis that causal mutations underlying psychiatric disorders have positive effects on reproductive success.

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“…Additionally, Lee et al estimated that 23% of variation in liability to schizophrenia is captured by single-nucleotide polymorphisms (SNPs) 5. For schizophrenia, some genetic factors were shared with other psychiatric disorders (bipolar disorder, major depressive disorder, autism spectrum disorders, and attention-deficit/hyperactivity disorder),6 and some genetic factors associated with its risk were overlapped with those associated with reproduction traits (eg, age at first birth) 7. In short, schizophrenia is highly polygenic 8…”

Section: Introductionmentioning

confidence: 99%

Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis

Yang

et al. 2016

NDT

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ObjectiveTo determine the relationships between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia using meta-analysis.MethodThe PubMed, Embase, and China National Knowledge Infrastructure databases were searched to identify relevant literature published up to February 2016. The allele contrast model was used. Stata software was used for statistical analysis, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated to evaluate the associations between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia. Meta-regression and publication bias, trim-and-fill, subgroup, sensitivity, cumulative, and fail-safe number analyses were also performed.ResultsThis meta-analysis included 81 studies. The rs1801028 and rs1799732 were associated with schizophrenia risk among Asians (P=0.04, OR =1.25, 95% CI =1.01–1.55; P<0.01, OR =0.76, 95% CI =0.63–0.92, respectively), while the rs6277 was associated with schizophrenia risk in Caucasians (P<0.01, OR=0.72, 95% CI =0.66–0.79). The rs1800497 was also associated with schizophrenia risk in population-based controls (P<0.01, OR =0.84, 95% CI =0.72–0.97). The rs6275, rs1079597, and rs1800498 were not associated with schizophrenia risk. In addition, meta-regression indicated that the controls may be sources of heterogeneity for the rs1801028 single-nucleotide polymorphism (SNP), while ethnicity may be sources of heterogeneity for the rs6277 SNP. Publication bias was significant for the rs1801028 SNP, and this result changed after the publication bias was adjusted using the trim-and-fill method.ConclusionThis meta-analysis demonstrated that the rs1801028 may be a risk factor for susceptibility to schizophrenia among Asians, while the rs1799732 may be a protective factor for that population. Large-sample studies are necessary to verify the results of this meta-analysis.

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Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Cited by 54 publications

References 32 publications

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

The genetic relationship between female reproductive traits and six psychiatric disorders

Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis

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