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The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.

The marine silicon cycle is intrinsically linked with carbon cycling in the oceans via biological production of silica by a wide range of organisms. The stable silicon isotopic composition (denoted by δ30Si) of siliceous microfossils extracted from sediment cores can be used as an archive of past oceanic silicon cycling. However, the silicon isotopic composition of biogenic silica has only been measured in diatoms, sponges and radiolarians, and isotopic fractionation relative to seawater is entirely unknown for many other silicifiers. Furthermore, the biochemical pathways and mechanisms that determine isotopic fractionation during biosilicification remain poorly understood. Here, we present the first measurements of the silicon isotopic fractionation during biosilicification by loricate choanoflagellates, a group of protists closely related to animals. We cultured two species of choanoflagellates, Diaphanoeca grandis and Stephanoeca diplocostata, which showed consistently greater isotopic fractionation (approximately −5 ‰ to −7 ‰) than cultured diatoms (−0.5 ‰ to −2.1 ‰). Instead, choanoflagellate silicon isotopic fractionation appears to be more similar to sponges grown under similar dissolved silica concentrations. Our results highlight that there is a taxonomic component to silicon isotope fractionation during biosilicification, possibly via a shared or related biochemical transport pathway. These findings have implications for the use of biogenic silica δ30Si produced by different silicifiers as proxies for past oceanic change.