statistics from other independent studies 13,17,18 , we identify novel host-microbiota interactions. Furthermore, we explore the impact of potential confounding factors in modulating these genetic effects and identify potential diet-dependent host-microbiota interactions. We further assess the potential causal relationships between the gut microbiome and dietary habits, biomarkers and disease using Mendelian randomization (MR). Finally, we carry out a power analysis showing how microbiome studies, even at the current sample size, are underpowered to reveal the complex genetic architecture by which host genetics regulates the gut microbiome. ResultsGenome-wide associations with bacterial taxa and pathways. We investigated 5.5 million common (minor allele frequency (MAF) > 0.05) genetic variants on all autosomes and the X chromosome using linear mixed models 19 to test their association with 207 taxa and 205 bacterial pathways in 7,738 individuals from the DMP cohort (Methods and Supplementary Table 1) 19 . There was no evidence for test statistic inflation (median genomic lambda 1.002 (range, 0.75-1.03) for taxa and 1.004 (range, 0.87-1.04) for pathways). We identified 37 single nucleotide polymorphism (SNP)trait associations at 24 independent loci at a genome-wide P value threshold of 5 × 10 −8 (Fig. 1 and Supplementary Table 2). Genetic variants at two loci passed the more stringent study-wide threshold of 1.89 × 10 −10 that accounts for the number of independent tests performed (Methods).The strongest signal was seen for rs182549 located in an intron of MCM6, a perfect proxy of rs4988235 (r 2 = 1, 1000 Genomes Project European populations), one of the variants known to regulate the LCT gene and responsible for lactase persistence in adults (ClinVar accession RCV000008124). The T allele of rs182549, which confers lactase persistence through a dominant model of inheritance, was found to be associated with decreased abundances of the species Bifidobacterium adolescentis (P = 7.6 × 10 −14 ) and Bifidobacterium longum (P = 3.2 × 10 −08 ), as well as decreased abundances of higher-level taxa (Supplementary Table 2 (ref. 5 )). Associations at this locus were also seen for other taxa of the same genus but at lower levels of significance (Bifidobacterium catenulatum, P = 3.9 × 10 −5 ) and for species of the Collinsella genus (Extended Data Fig. 1). The genetic association at the LCT locus has been previously described, albeit only at the genus level, in Dutch, UK and US cohorts 6,8,14 , as well as in a recent large-scale meta-analysis 13 .The second locus that passed study-wide significance consisted of genetic variants near the ABO gene. ABO encodes the BGAT protein, a histo-blood group ABO system transferase. Associations found at this locus include species Bifidobacterium bifidum (rs8176645, p = 5.5 × 10 −15 ) and Collinsella aerofaciens (rs550057, P = 2.0 × 10 −8 , r 2 = 0.59 with rs8176645 in 1000 Genomes Project Europeans) and higher-order taxa (rs550057, genus Collinsella, P = 9.3 × 10 −11 ; family Coriobacteriac...

Type 2 diabetes is one of the major chronic diseases accounting for a substantial proportion of disease burden in Western countries. The majority of the burden of type 2 diabetes is attributed to environmental risks and modifiable risk factors such as lifestyle. The environment we live in, and changes to it, can thus contribute substantially to the prevention of type 2 diabetes at a population level. The 'exposome' represents the (measurable) totality of environmental, i.e. nongenetic, drivers of health and disease. The external exposome comprises aspects of the built environment, the social environment, the physico-chemical environment and the lifestyle/food environment. The internal exposome comprises measurements at the epigenetic, transcript, proteome, microbiome or metabolome level to study either the exposures directly, the imprints these exposures leave in the biological system, the potential of the body to combat environmental insults and/or the biology itself. In this review, we describe the evidence for environmental risk factors of type 2 diabetes, focusing on both the general external exposome and imprints of this on the internal exposome. Studies provided established associations of air pollution, residential noise and area-level socioeconomic deprivation with an increased risk of type 2 diabetes, while neighbourhood walkability and green space are consistently associated with a reduced risk of type 2 diabetes. There is little or inconsistent evidence on the contribution of the food environment, other aspects of the social environment and outdoor temperature. These environmental factors are thought to affect type 2 diabetes risk mainly through mechanisms incorporating lifestyle factors such as physical activity or diet, the microbiome, inflammation or chronic stress. To further assess causality of these associations, future studies should focus on investigating the longitudinal effects of our environment (and changes to it) in relation to type 2 diabetes risk and whether these associations are explained by these proposed mechanisms.

Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89×10−10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5×10−8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.