Two publications in Nature Genetics: New genes and cell types found for intelligence and neuroticism

An international research team led by Professor Danielle Posthuma (VU / VUmc) has identified the genes, brain areas and cell types that are important in intelligence and neuroticism. Both studies have been published in Nature Genetics.

Intelligence - insight into the biological mechanisms

Intelligence is a highly heritable trait. It is well known that many genes are involved in intelligence, yet which genes what those are and what their function is until recently was unknown. Last year, the Posthuma group published a pioneering genetic study into intelligence in which more than 50 genes were found. In the current study more than 1000 specific genes are found, which allowed the team for the first time to implicate specific types of cells in the brain that are important for intelligence.

Future studies will be able to more specifically focus on the role of different types of cells in the brain and how the function of these cells leads to differences in cognitive functioning.

Protection against Alzheimer's

The study was conducted as part of a large collaboration in which genetic data from more than 260 thousand individuals were linked to scores on cognitive tests. In addition, large biological datasets were used to better understand the results. For example, external information on the expression of genes in specific types of cells was used to test whether genes of interest to intelligence are active in all cell types or in specific cell types. "We found very clear evidence that cells in the hippocampus and the somatosensory cortex play an important role in intelligence. The designation of these types of cells is an important step in unraveling the biological mechanism of intelligence.", says Posthuma.

Intelligence is associated with various other characteristics, such as attention disorders, depression, Alzheimer's dementia and schizophrenia. "A better understanding of the biological background of intelligence is also important for our understanding of these characteristics," says Jeanne Savage, as a postdoc working in the Posthuma group. "Our results also showed that there is a direct protective effect of intelligence on the risk for Alzheimer's dementia", adds Philip Jansen, who carried out some of the analyses for the study.

Neuroticism - Largest study ever

A second large-scale study, also published today in Nature Genetics, provides new indications for the genetic basis of neuroticism. Neuroticism is an important risk factor for psychiatric disorders such as depression, anxiety and schizophrenia, but it is also related to, for example, longevity and well-being.

This research, led by Posthuma and VUmc scientist Sophie van der Sluis, is the largest study ever on neuroticism. Because effects of specific genes on personality traits are usually small, the researchers studied genetic data of 449,484 individuals.

They found 124 new genetic regions that are related to differences between individuals in neuroticism. "This is a strong increase compared to previous studies (16 genetic regions) and shows that very large samples are enable the discovery of more of the genes involved," says Van der Sluis. The results suggest that genes associated with neuroticism are predominantly expressed in frontal brain areas, and mainly in three specific cell types. “The availability of large biological databases enabled us to study the role of specific cell types in neuroticism for the first time. This information is vital for follow-up investigations into the biological mechanisms underlying this personality trait”, says Philip Jansen, the PhD candidate who was responsible for a large part of the analyses conducted in this study.

Genetic overlap with depression

Since high scores on neuroticism often go hand in hand with depressive symptoms, the researchers also looked at the genetic overlap between neuroticism and depression. For depression, the researchers looked at genetic information in 688,809 individuals. They found 45 genetic regions for depression. A large part of it corresponded to the genetic regions for neuroticism. An earlier study by Mats Nagel, PhD candidate in the lab of Posthuma and van der Sluis, revealed two genetically distinct components for neuroticism. Nagel: “The current results clearly show that one component is genetically very similar to depression. This suggests that biological information on this component might be particularly relevant also in studying the genetics of depression”. These findings can contribute to the understanding of the biological relationship between these two properties and provide concrete tools for follow-up research.

Nagel M, Jansen PR, Stringer S, Watanabe K, de Leeuw CA, Bryois J, Savage JE, Hammerschlag AR, Skene N, Muñoz-Manchado AB, the 23andMe Research Team,  White TJH, Tiemeier H, Linnarsson S, Hjerling-Leffler J, Polderman TJC, Sullivan PF, van der Sluis S, Posthuma D. Meta-Analysis of Genome-wide Association Studies for Neuroticism in 449,484 Individuals Identifies Novel Genetic Loci and Pathways. Nature Genetics, published online June 25, 2018 DOI: 10.1038/s41588-018-0151-7

Genetic findings for intelligence, from Savage, Jansen et al Nature Genetics, 2018 Genetic findings for intelligence, from Savage, Jansen et al Nature Genetics, 2018

The study on intelligence can be accessed here:

Savage JE, Jansen PR,  Stringer S, Watanabe K, Bryois J, de Leeuw CA, Nagel M, Awasthi S, Barr PB, Coleman JRI, Grasby KL, Hammerschlag AR, Kaminski J, Karlsson R, Krapohl E, Lam M, Nygaard M, Reynolds CA, Trampush JW, Young H, Zabaneh D, Hägg S, Hansell NK, Karlsson IK, Linnarsson S, Montgomery GW, Munoz-Manchado AB, Quinlan EB, Schumann G, Skene N, Webb BT, White T, Arking DE, Attix DK, Avramopoulos D, Bilder RM, Bitsios P, Burdick KE, Cannon TD, Chiba-Falek O, Christoforou A, Cirulli ET, Congdon E, Corvin A, Davies G, Deary IJ, DeRosse P, Dickinson D, Djurovic S, Donohoe G, Drabant Conley E, Eriksson JG, Espeseth T, Freimer NA, Giakoumaki S, Giegling I, Gill M, Glahn DC, Hariri AR, Hatzimanolis A, Keller MC, Knowles E, Konte B, Lahti J, Le Hellard S, Lencz T, Liewald DC, London E, Lundervold AJ, Malhotra AK, Melle I, Morris D, Need AC, Ollier W, Palotie A, Payton A, Pendleton N, Poldrack RA, Räikkönen K, Reinvang I, Roussos P, Rujescu D, Sabb FW, Scult MA, Smeland OB, Smyrnis N, Starr JM, Steen VM, Stefanis NC, Straub RE, Sundet K, Tiemeier H, Voineskos AN, Weinberger DR, Widen E, Yu J, Abecasis G, Andreassen OA, Breen G, Christiansen L, Debrabant B, Dick DM, Heinz A, Hjerling-Leffler J, Ikram MA, Kendler KS, Martin NG, Medland SE, Pedersen NL, Plomin R, Polderman TJC, Ripke S, van der Sluis S, Sullivan PF, Vrieze SI, Wright MJ, Posthuma D. Genome-wide association meta-analysis (N=269,867) identifies new genetic and functional links to intelligence. Nature Genetics, published online June 25, 2018 DOI 10.1038/s41588-018-0152-6.

Genetic findings for neuroticism, from Nagel, Jansen et al Nature Genetics, 2018 Genetic findings for neuroticism, from Nagel, Jansen et al Nature Genetics, 2018

The study on neuroticism can be accessed here: