Novel genetic loci associated with hippocampal volume

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g ¼ À 0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Breaking down the genetics of depression using brain endophenotypes

“…In comparison, the 8 ICV SNPs explained 0.099 to 0.27% of the variance [78], the 6 hippocampus SNPs 0.092 to 0.32% [77], the 4 putamen SNPs 0.14 to 0.32, while the 1 SNP associated with caudate explained 0.11% of the trait variance [76]. These results are summarised in Figure Our results align with the hypothesis of a simpler genetic architecture of brain structural phenotypes compared to psychiatric diagnoses.…”

“…We included SNPs from the largest GWAS reporting significant associations with MDD (female only, recurrent) [15], schizophrenia [79], Alzheimer's disease [596], volumes of the subcortical structures: putamen, caudate nucleus, and hippocampus, as well as [76], ICV and hippocampal volume [77], We also included SNPs from the GWAS for rheumatoid arthritis [597] to check if our results align with the conclusions from the Bayesian approach [592,594,598]. SNPs used and estimated ! "…”

“…Aside from the fairly provocative tone of the paper, which may explain some of the shortcuts in the conclusions (and the Donald Rumsfeld's citation), we aimed at investigating the claim that brain phenotypes are indeed as complex as psychiatric disorders. We reviewed in Chapter 9 the most recent evidence from the largest imaging GWAS (ENIGMA and CHARGE consortia [76][77][78]506]) and the most recent GWAS on a selection of clinical phenotypes: MDD [15], SCZ [79], Alzheimer's disease [596] and Rheumatoid Arthritis (RA) [597,625]. We showed that the effect sizes of the genome-wide significant SNPs were markedly greater for brain structural phenotypes (ICV, hippocampal and putamen volumes) than for clinical phenotypes.…”

“…Finally we came back to the hypothesised simpler genetic architecture of endophenotypes compared to psychiatric diagnoses [16]. We contrasted published SNP effect sizes on brain phenotype (ICV, hippocampal volume, putamen, nucleus accumbens) [76][77][78] with those of psychiatric traits (depression, schizophrenia) [15,79] and evaluated if they align with the theory. BATS [35,80]), which began in 1992 when twins were recruited from primary and secondary schools in the greater Brisbane area via media appeals and by word of mouth.…”

Aging Mindfully to Minimize Cognitive Decline

“…Similarly, improving (or at least preserved) performance into older age has been reported for tasks relying on accrued knowledge and verbal abilities (Park et al 2002;Salthouse 2012). It is also worth noting that the impact of aging on cognition is modulated by health factors (e.g., anxiety, blood pressure) and lifestyle choices (e.g., exercise, diet) in a sex-and brain region-specific fashion, and genetic variations will lead to additional age interactions due to their impact on the brain structure, cognitive abilities, vulnerability to neurodegeneration, and cognitive decline (Coffey et al 1998;Hibar et al 2017;IOM 2015;Kassem et al 2017;Reinvang et al 2013;Salthouse 2012;Xu et al 2000). Altogether, this makes it extremely difficult to compare findings across different studies when looking at the efficacy of possible age-defying interventions, such as meditation.…”