[From genetic findings to clinical practice in psychiatry: how genetics may enable Precision Psychiatry]. / Van genetische bevindingen naar de klinische praktijk van de psychiater: hoe genetica precisiepsychiatrie mogelijk kan maken.

BACKGROUND: Most psychiatric disorders are characterized by a complex genetic background where many common variants are involved. Nowadays, we are able to 'read' these variants, test for their association with phenotypes in genome-wide association studies (GWAS), and perform further downstream analyses. However, the impact of such findings on clinical psychiatry has remained largely unclear.
AIM: To provide new insight into the degree of genetic overlap between psychiatric disorders and neurological disorders. And to investigate how genetic findings may impact clinical practice in psychiatry.
METHOD: Bioinformatics and statistical methods were applied to perform analyses in large genetic datasets. In particular, we focused on: pathway analyses in schizophrenia; a multivariate GWAS of stress and trauma phenotypes; and genetic overlap analyses between amyotrophic lateral sclerosis (ALS) and schizophrenia. Finally, we assessed for which psychiatric disorders genetic findings are most likely to impact clinical practice in the near future.
RESULTS: First, we found enrichment of common genetic variants associated with schizophrenia in synaptic signalling pathways relating to dopaminergic, acetylcholinergic and glutamatergic neurons. Second, we found that ALS and schizophrenia partly share common genetic risk. And third, we outline the clinical relevance of genetic cross-disorder studies in psychiatry, and posit that these studies have meaning for diagnostics, prognostics and treatment prediction in psychiatry.
CONCLUSION: The summarized and previous genetic studies into psychiatric disorders will hopefully soon enable precision psychiatry, as genetics is a powerful tool to elucidate individualized risk profiles of patients and their responses to psychotropic medication. Genetic counselling allows clinicians to carefully balance the wide range of considerations in those patients and relatives with questions related to genetic underpinnings of disease and treatment response.

Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels.

Treatment with serotonin reuptake inhibitors (SSRI) has been associated with an increased risk of preterm birth, but causality remains unclear. While placental CRH production is correlated with gestational length and preterm birth, it has been difficult to establish if psychological stress or mental health problems are associated with increased CRH levels. This study compared second trimester CRH serum concentrations in pregnant women on SSRI treatment (n=207) with untreated depressed women (n=56) and controls (n=609). A secondary aim was to investigate the combined effect of SSRI treatment and CRH levels on gestational length and risk for preterm birth. Women on SSRI treatment had significantly higher second trimester CRH levels than controls, and untreated depressed women. CRH levels and SSRI treatment were independently associated with shorter gestational length. The combined effect of SSRI treatment and high CRH levels yielded the highest risk estimate for preterm birth. SSRI treatment during pregnancy is associated with increased CRH levels. However, the elevated risk for preterm birth in SSRI users appear not to be mediated by increased placental CRH production, instead CRH appear as an independent risk factor for shorter gestational length and preterm birth.

Gene Expression in Placentas From Nondiabetic Women Giving Birth to Large for Gestational Age Infants.

Gestational diabetes, obesity, and excessive weight gain are known independent risk factors for the birth of a large for gestational age (LGA) infant. However, only 1 of the 10 infants born LGA is born by mothers with diabetes or obesity. Thus, the aim of the present study was to compare placental gene expression between healthy, nondiabetic mothers (n = 22) giving birth to LGA infants and body mass index-matched mothers (n = 24) giving birth to appropriate for gestational age infants. In the whole gene expression analysis, only 29 genes were found to be differently expressed in LGA placentas. Top upregulated genes included insulin-like growth factor binding protein 1, aminolevulinate δ synthase 2, and prolactin, whereas top downregulated genes comprised leptin, gametocyte-specific factor 1, and collagen type XVII α 1. Two enriched gene networks were identified, namely, (1) lipid metabolism, small molecule biochemistry, and organismal development and (2) cellular development, cellular growth, proliferation, and tumor morphology.

Serotonin 1A receptors and sexual behavior in a genetic model of depression.

The Flinder Sensitive Line (FSL) is a rat strain that displays distinct behavioral and neurochemical features of major depression. Chronic selective serotonin reuptake inhibitors (SSRIs) are able to reverse these symptoms in FSL rats. It is well known that several abnormalities in the serotonergic system have been found in FSL rats, including increased 5-HT brain tissue levels and reduced 5-HT synthesis. SSRIs are known to exert (part of) their effects by desensitization of the 5-HT1A receptor and FSL rats appear to have lower 5-HT1A receptor densities compared with Flinder Resistant Line (FRL) rats. We therefore studied the sensitivity of this receptor on the sexual behavior performance in both FRL and FSL rats. First, basal sexual performance was studied after saline treatment followed by treatment of two different doses of the 5-HT1A receptor agonist ±8-OH-DPAT. Finally we measured the effect of a 5-HT1A receptor antagonist to check for specificity of the 5-HT1A receptor activation. Our results show that FSL rats have higher ejaculation frequencies compared with FRL rats which do not fit with a more depressive-like phenotype. Moreover FRL rats are more sensitive to effects of ±8-OH-DPAT upon EL and IF than FSL rats. The blunted response of FSL rats to the effects of ±8-OH-DPAT may be due to lower densities of 5-HT1A receptors.