"The markets' regular macro concerns -- Brexit and the US-China trade war -- (are) weighing heavy on investors' minds," noted Spreadex analyst Connor Campbell.
In Europe, Frankfurt fell the heaviest with Bayer shares tumbling after a US jury ruled its weedkiller Roundup was a "substantial factor" in an amateur gardener's cancer.
Later Wednesday, the Federal Reserve's March policy meeting concludes, with analysts predicting it will announce a slower pace of interest rate hikes as the world's biggest economy shows signs of softening amid trade tensions.
"Global equities are either trading mixed or are lower as investors adopt a cautious approach ahead of the Fed's decision and further news on China-US trade talks, where negotiators are said to remain at odds," said Oanda analyst Dean Popplewell.
General optimism about the outlook for the tariffs negotiations has helped propel equities higher across the world this year -- offsetting concerns about the outlook for the global economy.
- Dealers spooked -
But dealers have been spooked by a report that some US officials are feeling some pushback from China on a number of demands, including on the crucial issue of intellectual property.
The unnamed negotiators said the Chinese side was growing concerned at the lack of assurances that US duties would be removed, according to the Bloomberg story.
US Trade Representative Robert Lighthizer and Treasury Secretary Steven Mnuchin will return to Beijing next week to resume talks.
Adding to unease on trading floors is continued uncertainty surrounding Britain's drawn-out departure from the European Union.
Prime Minister Theresa May is expected to ask the bloc for an extension of the March 29 deadline for leaving, having seen her exit proposals killed off by MPs.
The pound wobbled against the euro and dollar in the absence of fresh developments.
"The pound is drifting as the market eyes British Prime Minister Theresa May's efforts to draft a request for an extension to conclude a Brexit deal that could pass parliament," added Popplewell.
Observers expect the exit date to be put back but there is a concern that it could be rejected, leaving Britain to crash out of the EU without a deal.
- 'Floodgates could open' for Bayer -
Frankfurt stocks meanwhile sank 1.3 percent as the threat to German giant Bayer and its subsidiary Monsanto from US litigation swelled.
A wave of lawsuits has put pressure on Bayer since its $63-billion takeover of Monsanto last year, spooking investors who worry damages payouts could escalate if the firm fails to convince courts its product is safe.
Markets shuddered after a federal court finding Tuesday that Roundup was behind the non-Hodgkin's lymphoma suffered by 70-year-old Edwin Hardeman, who used the product for decades on the garden at his California home.
"This in the second time in one year a jury has come to that conclusion.
"This could open the floodgates to further cases, and the group might have to set aside vast sums of money for potential cases."
The news sent Bayer shares nosediving 12.2 percent to 61.20 euros.