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Negative short-range genomic autocorrelation of causal effects on human complex traits

By Armin P. Schoech, Omer Weissbrod, Luke Jen O'Connor, Nick Patterson, Huwenbo Shi, Yakir A Reshef, Alkes Price

Posted 24 Sep 2020
bioRxiv DOI: 10.1101/2020.09.23.310748

Most models of complex trait genetic architecture assume that signed causal effect sizes of each SNP (defined with respect to the minor allele) are uncorrelated with those of nearby SNPs, but it is currently unknown whether this is the case. We develop a new method, autocorrelation LD regression (ACLR), for estimating the genome-wide autocorrelation of causal minor allele effect sizes as a function of genomic distance. Our method estimates these autocorrelations by regressing the products of summary statistics on distance-dependent LD scores. We determined that ACLR robustly assesses the presence or absence of nonzero autocorrelation, producing unbiased estimates with well-calibrated standard errors in null simulations regardless of genetic architecture; if true autocorrelation is nonzero, ACLR correctly detects its sign, although estimates of the autocorrelation magnitude are susceptible to bias in cases of certain genetic architectures. We applied ACLR to 31 diseases and complex traits from the UK Biobank (average N =331K), meta-analyzing results across traits. We determined that autocorrelations were significantly negative at distances of 1-50bp ( P = 8 × 10−6, point estimate −0.35 ±0.08) and 50-100bp ( P = 2 × 10−3, point estimate −0.33 ± 0.11). We show that the autocorrelation is primarily driven by pairs of SNPs in positive LD, which is consistent with the expectation that linked SNPs with opposite effects are less impacted by natural selection. Our findings suggest that this mechanism broadly affects complex trait genetic architectures, and we discuss implications for association mapping, heritability estimation, and genetic risk prediction. ### Competing Interest Statement The authors have declared no competing interest.

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